Transcription factor networks in cellular quiescence

Transcription factor networks in cellular quiescence

Play all audios:

Loading...

ABSTRACT Many of the cells in mammalian tissues are in a reversible quiescent state; they are not dividing, but retain the ability to proliferate in response to extracellular signals.


Quiescence relies on the activities of transcription factors (TFs) that orchestrate the repression of genes that promote proliferation and establish a quiescence-specific gene expression


program. Here we discuss how the coordinated activities of TFs in different quiescent stem cells and differentiated cells maintain reversible cell cycle arrest and establish cell-protective


signalling pathways. We further cover the emerging mechanisms governing the dysregulation of quiescence TF networks with age. We explore how recent developments in single-cell technologies


have enhanced our understanding of quiescence heterogeneity and gene regulatory networks. We further discuss how TFs and their activities are themselves regulated at the RNA, protein and


chromatin levels. Finally, we summarize the challenges associated with defining TF networks in quiescent cells. Access through your institution Buy or subscribe This is a preview of


subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value


online-access subscription $29.99 / 30 days cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more


Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS:


* Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS REGULATION OF ADULT STEM CELL QUIESCENCE AND ITS


FUNCTIONS IN THE MAINTENANCE OF TISSUE INTEGRITY Article 15 March 2023 AN INTERMEDIATE RB–E2F ACTIVITY STATE SAFEGUARDS PROLIFERATION COMMITMENT Article Open access 26 June 2024 LRIG1 IS A


GATEKEEPER TO EXIT FROM QUIESCENCE IN ADULT NEURAL STEM CELLS Article Open access 10 May 2021 REFERENCES * Basu, S., Greenwood, J., Jones, A. W. & Nurse, P. Core control principles of


the eukaryotic cell cycle. _Nature_ 607, 381–386 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Coller, H. A., Sang, L. & Roberts, J. M. A new description of cellular quiescence.


_PLoS Biol._ 4, e83 (2006). PubMed  PubMed Central  Google Scholar  * Marescal, O. & Cheeseman, I. M. Cellular mechanisms and regulation of quiescence. _Dev. Cell_ 55, 259–271 (2020).


CAS  PubMed  PubMed Central  Google Scholar  * De Morree, A. & Rando, T. A. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. _Nat. Rev.


Mol. Cell Biol._ 24, 334–354 (2023). PubMed  PubMed Central  Google Scholar  * Sun, S. & Gresham, D. Cellular quiescence in budding yeast. _Yeast_ 38, 12–29 (2021). PubMed  Google


Scholar  * Urban, N., Blomfield, I. M. & Guillemot, F. Quiescence of adult mammalian neural stem cells: a highly regulated rest. _Neuron_ 104, 834–848 (2019). CAS  PubMed  Google Scholar


  * Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. _Nat. Rev. Immunol._ 20, 55–70 (2020). CAS  PubMed  Google Scholar  * Ricard, N.,


Bailly, S., Guignabert, C. & Simons, M. The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy. _Nat. Rev. Cardiol._ 18, 565–580 (2021). CAS 


PubMed  PubMed Central  Google Scholar  * Mitra, M., Ho, L. D. & Coller, H. A. An in vitro model of cellular quiescence in primary human dermal fibroblasts. _Methods Mol. Biol._ 1686,


27–47 (2018). CAS  PubMed  PubMed Central  Google Scholar  * Lemons, J. M. et al. Quiescent fibroblasts exhibit high metabolic activity. _PLoS Biol._ 8, e1000514 (2010). PubMed  PubMed


Central  Google Scholar  * Legesse-Miller, A. et al. Quiescent fibroblasts are protected from proteasome inhibition-mediated toxicity. _Mol. Biol. Cell_ 23, 3566–3581 (2012). CAS  PubMed 


PubMed Central  Google Scholar  * Min, M. & Spencer, S. L. Spontaneously slow-cycling subpopulations of human cells originate from activation of stress-response pathways. _PLoS Biol._


17, e3000178 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Tumpel, S. & Rudolph, K. L. Quiescence: good and bad of stem cell aging. _Trends Cell Biol._ 29, 672–685 (2019).


PubMed  Google Scholar  * Gustafson, C. E. Naive T cell quiescence in immune aging. _Adv. Geriatr. Med. Res._ 3, e210015 (2021). PubMed  PubMed Central  Google Scholar  * Mitra, M. et al.


Alternative polyadenylation factors link cell cycle to migration. _Genome Biol._ 19, 176 (2018). PubMed  PubMed Central  Google Scholar  * Bediaga, N. G. et al. Multi-level remodelling of


chromatin underlying activation of human T cells. _Sci. Rep._ 11, 528 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Phan, T. G. & Croucher, P. I. The dormant cancer cell life


cycle. _Nat. Rev. Cancer_ 20, 398–411 (2020). CAS  PubMed  Google Scholar  * Fischer, M., Schade, A. E., Branigan, T. B., Muller, G. A. & DeCaprio, J. A. Coordinating gene expression


during the cell cycle. _Trends Biochem. Sci._ 47, 1009–1022 (2022). CAS  PubMed  Google Scholar  * Malumbres, M. Cyclin-dependent kinases. _Genome Biol._ 15, 122 (2014). PubMed  PubMed


Central  Google Scholar  * Marceau, A. H. et al. Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. _Nat. Commun._ 7, 12301 (2016). CAS  PubMed  PubMed


Central  Google Scholar  * Herrera, J. L. & Komatsu, M. Akt3 activation by R-Ras in an endothelial cell enforces quiescence and barrier stability of neighboring endothelial cells via


Jagged1. _Cell Rep._ 43, 113837 (2024). CAS  PubMed  PubMed Central  Google Scholar  * Llorens-Bobadilla, E. et al. Single-cell transcriptomics reveals a population of dormant neural stem


cells that become activated upon brain injury. _Cell Stem Cell_ 17, 329–340 (2015). CAS  PubMed  Google Scholar  * Sang, L., Coller, H. A. & Roberts, J. M. Control of the reversibility


of cellular quiescence by the transcriptional repressor HES1. _Science_ 321, 1095–1100 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Sueda, R., Imayoshi, I., Harima, Y. &


Kageyama, R. High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain. _Genes Dev._ 33, 511–523 (2019). CAS  PubMed 


PubMed Central  Google Scholar  * Murley, A. & Dillin, A. Macroautophagy in quiescent and senescent cells: a pathway to longevity? _Trends Cell Biol._ 33, 495–504 (2023). CAS  PubMed 


Google Scholar  * Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. _EMBO J._ 33, 2782–2797 (2014). CAS 


PubMed  PubMed Central  Google Scholar  * Calatayud-Baselga, I. et al. Autophagy drives the conversion of developmental neural stem cells to the adult quiescent state. _Nat. Commun._ 14,


7541 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging.


_Science_ 359, 1277–1283 (2018). CAS  PubMed  PubMed Central  Google Scholar  * Liang, R. et al. Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.


_Cell Stem Cell_ 26, 359–376.e7 (2020). CAS  PubMed  PubMed Central  Google Scholar  * Martina, J. A. et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal


biogenesis, and clearance of cellular debris. _Sci. Signal_ 7, ra9 (2014). PubMed  PubMed Central  Google Scholar  * Audesse, A. J. et al. FOXO3 directly regulates an autophagy network to


functionally regulate proteostasis in adult neural stem cells. _PLoS Genet._ 15, e1008097 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Soh, R., Hardy, A. & Zur Nieden, N. I.


The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness. _Free Radic. Biol. Med._ 169, 224–237 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Tzivion,


G., Dobson, M. & Ramakrishnan, G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins. _Biochim. Biophys. Acta_ 1813, 1938–1945 (2011). CAS  PubMed  Google Scholar  *


Johnson, E. L., Robinson, D. G. & Coller, H. A. Widespread changes in mRNA stability contribute to quiescence-specific gene expression patterns in a fibroblast model of quiescence. _BMC


Genomics_ 18, 123 (2017). PubMed  PubMed Central  Google Scholar  * Baghdadi, M. B. et al. Reciprocal signalling by Notch–Collagen V–CALCR retains muscle stem cells in their niche. _Nature_


557, 714–718 (2018). CAS  PubMed  PubMed Central  Google Scholar  * Khurana, S. et al. Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin–Itgav axis.


_Nat. Commun._ 7, 13500 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Cho, I. J. et al. Mechanisms, hallmarks, and implications of stem cell quiescence. _Stem Cell Rep._ 12,


1190–1200 (2019). CAS  Google Scholar  * Van Velthoven, C. T. J., de Morree, A., Egner, I. M., Brett, J. O. & Rando, T. A. Transcriptional profiling of quiescent muscle stem cells in


vivo. _Cell Rep._ 21, 1994–2004 (2017). PubMed  PubMed Central  Google Scholar  * Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem


cells during the process of self-renewal. _Stem Cell Rep._ 2, 414–426 (2014). CAS  Google Scholar  * Sousa-Victor, P., Garcia-Prat, L. & Munoz-Canoves, P. Control of satellite cell


function in muscle regeneration and its disruption in ageing. _Nat. Rev. Mol. Cell Biol._ 23, 204–226 (2022). CAS  PubMed  Google Scholar  * Loreti, M. & Sacco, A. The jam session


between muscle stem cells and the extracellular matrix in the tissue microenvironment. _NPJ Regen. Med._ 7, 16 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Relaix, F. et al.


Perspectives on skeletal muscle stem cells. _Nat. Commun._ 12, 692 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Rayagiri, S. S. et al. Basal lamina remodeling at the skeletal


muscle stem cell niche mediates stem cell self-renewal. _Nat. Commun._ 9, 1075 (2018). PubMed  PubMed Central  Google Scholar  * Bjornson, C. R. et al. Notch signaling is necessary to


maintain quiescence in adult muscle stem cells. _Stem Cells_ 30, 232–242 (2012). CAS  PubMed  Google Scholar  * Low, S., Barnes, J. L., Zammit, P. S. & Beauchamp, J. R. Delta-like 4


activates Notch 3 to regulate self-renewal in skeletal muscle stem cells. _Stem Cells_ 36, 458–466 (2018). CAS  PubMed  Google Scholar  * Von Maltzahn, J., Jones, A. E., Parks, R. J. &


Rudnicki, M. A. Pax7 is critical for the normal function of satellite cells in adult skeletal muscle. _Proc. Natl Acad. Sci. USA_ 110, 16474–16479 (2013). Google Scholar  * Agarwal, M.,


Bharadwaj, A. & Mathew, S. J. TLE4 regulates muscle stem cell quiescence and skeletal muscle differentiation. _J. Cell Sci._ 135, jcs256008 (2022). CAS  PubMed  Google Scholar  *


Aloysius, A., DasGupta, R. & Dhawan, J. The transcription factor Lef1 switches partners from β-catenin to Smad3 during muscle stem cell quiescence. _Sci. Signal_ 11, eaan3000 (2018).


PubMed  Google Scholar  * Lacorazza, H. D. et al. The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. _Cancer Cell_ 9, 175–187 (2006). CAS  PubMed 


Google Scholar  * Chen, Z., Guo, Q., Song, G. & Hou, Y. Molecular regulation of hematopoietic stem cell quiescence. _Cell. Mol. Life Sci._ 79, 218 (2022). CAS  PubMed  PubMed Central 


Google Scholar  * Seshadri, M. & Qu, C. K. Microenvironmental regulation of hematopoietic stem cells and its implications in leukemogenesis. _Curr. Opin. Hematol._ 23, 339–345 (2016).


CAS  PubMed  PubMed Central  Google Scholar  * Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. _Cell Stem Cell_ 4, 37–48 (2009). CAS  PubMed  PubMed Central  Google Scholar


  * Hsu, T., Trojanowska, M. & Watson, D. K. Ets proteins in biological control and cancer. _J. Cell. Biochem._ 91, 896–903 (2004). CAS  PubMed  PubMed Central  Google Scholar  * Chavez,


J. S. et al. PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress. _J. Exp. Med._ 218, e20201169 (2021). CAS  PubMed  PubMed Central  Google


Scholar  * Hu, M. et al. Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy. _Leukemia_ 37, 1361–1374 (2023). CAS  PubMed  Google


Scholar  * Maybury-Lewis, S. Y. et al. Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age. _Aging Cell_


20, e13499 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Llorente, V., Velarde, P., Desco, M. & Gomez-Gaviro, M. V. Current understanding of the neural stem cell niches. _Cells_


11, 3002 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Lampada, A. & Taylor, V. Notch signaling as a master regulator of adult neurogenesis. _Front. Neurosci._ 17, 1179011


(2023). PubMed  PubMed Central  Google Scholar  * Engler, A. et al. Notch2 signaling maintains NSC quiescence in the murine ventricular-subventricular zone. _Cell Rep._ 22, 992–1002 (2018).


CAS  PubMed  Google Scholar  * Ehm, O. et al. RBPJκ-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. _J. Neurosci._ 30, 13794–13807


(2010). CAS  PubMed  PubMed Central  Google Scholar  * Garcia-Corzo, L. et al. The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem


cell quiescence. _Front. Cell Dev. Biol._ 10, 912319 (2022). PubMed  PubMed Central  Google Scholar  * Cheng, M., Nie, Y., Song, M., Chen, F. & Yu, Y. Forkhead box O proteins: steering


the course of stem cell fate. _Cell Regen._ 13, 7 (2024). CAS  PubMed  PubMed Central  Google Scholar  * Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. _Cell Stem Cell_


5, 527–539 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Calderon, D. et al. Landscape of stimulation-responsive chromatin across diverse human immune cells. _Nat. Genet._ 51,


1494–1505 (2019). CAS  PubMed  PubMed Central  Google Scholar  * Kye, Y. C. et al. STAT1 maintains naive CD8+ T cell quiescence by suppressing the type I IFN–STAT4–mTORC1 signaling axis.


_Sci. Adv._ 7, eabg8764 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Roychoudhuri, R. et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to


enhancers. _Nat. Immunol._ 17, 851–860 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Feng, X. et al. Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the


quiescence of naive T cells. _Nat. Immunol._ 12, 544–550 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Hedrick, S. M., Hess Michelini, R., Doedens, A. L., Goldrath, A. W. &


Stone, E. L. FOXO transcription factors throughout T cell biology. _Nat. Rev. Immunol._ 12, 649–661 (2012). CAS  PubMed  Google Scholar  * Stahl, M. et al. The forkhead transcription factor


FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. _J. Immunol._ 168, 5024–5031 (2002). CAS  PubMed  Google Scholar  * Feng, X. et al. Foxp1 is an essential transcriptional


regulator for the generation of quiescent naive T cells during thymocyte development. _Blood_ 115, 510–518 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Garaud, S. et al. FOXP1 is


a regulator of quiescence in healthy human CD4+ T cells and is constitutively repressed in T cells from patients with lymphoproliferative disorders. _Eur. J. Immunol._ 47, 168–179 (2017).


CAS  PubMed  Google Scholar  * Andrade, J. et al. Control of endothelial quiescence by FOXO-regulated metabolites. _Nat. Cell Biol._ 23, 413–423 (2021). CAS  PubMed  PubMed Central  Google


Scholar  * Mastej, V., Axen, C., Wary, A., Minshall, R. D. & Wary, K. K. A requirement for Krüppel like factor-4 in the maintenance of endothelial cell quiescence. _Front. Cell Dev.


Biol._ 10, 1003028 (2022). PubMed  PubMed Central  Google Scholar  * Dryden, N. H. et al. The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear


factor (NF)-κB p65. _J. Biol. Chem._ 287, 12331–12342 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Payne, S., Neal, A. & De Val, S. Transcription factors regulating


vasculogenesis and angiogenesis. _Dev. Dyn._ 253, 28–58 (2024). CAS  PubMed  Google Scholar  * Wei, G. et al. Ets1 and Ets2 are required for endothelial cell survival during embryonic


angiogenesis. _Blood_ 114, 1123–1130 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Oda, N., Abe, M. & Sato, Y. ETS-1 converts endothelial cells to the angiogenic phenotype by


inducing the expression of matrix metalloproteinases and integrin β3. _J. Cell. Physiol._ 178, 121–132 (1999). CAS  PubMed  Google Scholar  * Lendahl, U., Muhl, L. & Betsholtz, C.


Identification, discrimination and heterogeneity of fibroblasts. _Nat. Commun._ 13, 3409 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Liu, H., Adler, A. S., Segal, E. & Chang,


H. Y. A transcriptional program mediating entry into cellular quiescence. _PLoS Genet._ 3, e91 (2007). PubMed  PubMed Central  Google Scholar  * Lee, K. W., Yeo, S. Y., Sung, C. O. &


Kim, S. H. Twist1 is a key regulator of cancer-associated fibroblasts. _Cancer Res._ 75, 73–85 (2015). CAS  PubMed  Google Scholar  * Yeo, S. Y. et al. A positive feedback loop bi-stably


activates fibroblasts. _Nat. Commun._ 9, 3016 (2018). PubMed  PubMed Central  Google Scholar  * Kumar, R., Tripathi, R., Sinha, N. R. & Mohan, R. R. Transcriptomic landscape of quiescent


and proliferating human corneal stromal fibroblasts. _Exp. Eye Res._ 248, 110073 (2024). CAS  PubMed  Google Scholar  * Lin, H., Ye, Z., Xu, R., Li, X. E. & Sun, B. The transcription


factor JUN is a major regulator of quiescent pancreatic stellate cell maintenance. _Gene_ 851, 147000 (2023). CAS  PubMed  Google Scholar  * Zhang, S. et al. ATF3 induction prevents


precocious activation of skeletal muscle stem cell by regulating H2B expression. _Nat. Commun._ 14, 4978 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Rodriguez-Fraticelli, A. E. et


al. Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis. _Nature_ 583, 585–589 (2020). CAS  PubMed  PubMed Central  Google Scholar  * Zhou, P. et al. Single-cell CRISPR


screens in vivo map T cell fate regulomes in cancer. _Nature_ 624, 154–163 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Fomicheva, M. & Macara, I. G. Genome-wide CRISPR screen


identifies noncanonical NF-κB signaling as a regulator of density-dependent proliferation. _eLife_ 9, e63603 (2020). CAS  PubMed  PubMed Central  Google Scholar  * Bendixen, S. M. et al.


Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module. _J. Hepatol._ 80, 467–481 (2024). CAS  PubMed  Google Scholar  * Dell’Orso, S. et al.


Single cell analysis of adult mouse skeletal muscle stem cells in homeostatic and regenerative conditions. _Development_ 146, dev174177 (2019). PubMed  PubMed Central  Google Scholar  *


Barruet, E. et al. Functionally heterogeneous human satellite cells identified by single cell RNA sequencing. _eLife_ 9, e51576 (2020). CAS  PubMed  PubMed Central  Google Scholar  * De


Micheli, A. J., Spector, J. A., Elemento, O. & Cosgrove, B. D. A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell


populations. _Skelet. Muscle_ 10, 19 (2020). PubMed  PubMed Central  Google Scholar  * Dong, A. et al. Global chromatin accessibility profiling analysis reveals a chronic activation state in


aged muscle stem cells. _iScience_ 25, 104954 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Okafor, A. E. et al. Single-cell chromatin accessibility profiling reveals a


self-renewing muscle satellite cell state. _J. Cell Biol._ 222, e202211073 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Lee, S., An, L., Soloway, P. D. & White, A. C. Dynamic


regulation of chromatin accessibility during melanocyte stem cell activation. _Pigment Cell Melanoma Res._ 36, 531–541 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Harris, L. et


al. Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population. _Cell Stem Cell_ 28, 863–876.e6 (2021). CAS  PubMed  PubMed Central 


Google Scholar  * Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. _Cell_ 176, 1407–1419.e14 (2019). CAS  PubMed  Google Scholar


  * Palmer, J. W. et al. Quiescence and aging of melanocyte stem cells and a novel association with programmed death-ligand 1. _iScience_ 27, 110908 (2024). CAS  PubMed  PubMed Central 


Google Scholar  * Lai, Y. et al. Multimodal cell atlas of the ageing human skeletal muscle. _Nature_ 629, 154–164 (2024). CAS  PubMed  PubMed Central  Google Scholar  * Garcia-Prat, L. et


al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. _Nat. Cell Biol._ 22, 1307–1318 (2020). CAS  PubMed  Google Scholar  * Durand, A. et al. Type 1 interferons


and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice. _Nat. Commun._ 15, 1718 (2024). CAS  PubMed  PubMed Central  Google Scholar  * Cao, W. et al. TRIB2


safeguards naive T cell homeostasis during aging. _Cell Rep._ 42, 112195 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Chan, M. et al. Novel insights from a multiomics dissection of


the Hayflick limit. _eLife_ 11, e70283 (2022). CAS  PubMed  PubMed Central  Google Scholar  * Marthandan, S., Priebe, S., Hemmerich, P., Klement, K. & Diekmann, S. Long-term quiescent


fibroblast cells transit into senescence. _PLoS ONE_ 9, e115597 (2014). PubMed  PubMed Central  Google Scholar  * Zou, Z. et al. A single-cell transcriptomic atlas of human skin aging. _Dev.


Cell_ 56, 383–397.e8 (2021). CAS  PubMed  Google Scholar  * Gasek, N. S., Kuchel, G. A., Kirkland, J. L. & Xu, M. Strategies for targeting senescent cells in human disease. _Nat. Aging_


1, 870–879 (2021). PubMed  PubMed Central  Google Scholar  * Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. _Nature_ 506, 316–321 (2014).


CAS  PubMed  Google Scholar  * Yue, L., Wan, R., Luan, S., Zeng, W. & Cheung, T. H. Dek modulates global intron retention during muscle stem cells quiescence exit. _Dev. Cell_ 53,


661–676.e6 (2020). CAS  PubMed  Google Scholar  * De Morree, A. et al. Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function. _Science_ 366, 734–738 (2019).


PubMed  PubMed Central  Google Scholar  * Li, H. B. et al. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. _Nature_ 548, 338–342 (2017). CAS 


PubMed  PubMed Central  Google Scholar  * Wolf, T. et al. Dynamics in protein translation sustaining T cell preparedness. _Nat. Immunol._ 21, 927–937 (2020). CAS  PubMed  PubMed Central 


Google Scholar  * Tullai, J. W., Tacheva, S., Owens, L. J., Graham, J. R. & Cooper, G. M. AP-1 is a component of the transcriptional network regulated by GSK-3 in quiescent cells. _PLoS


ONE_ 6, e20150 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Zhang, L. et al. The CalcR–PKA–Yap1 axis is critical for maintaining quiescence in muscle stem cells. _Cell Rep._ 29,


2154–2163.e5 (2019). CAS  PubMed  Google Scholar  * Yang, J. et al. Mecp2 fine-tunes quiescence exit by targeting nuclear receptors. _eLife_ 12, RP89912 (2024). PubMed  PubMed Central 


Google Scholar  * Sincennes, M. C. et al. Acetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice. _Nat. Commun._ 12, 3253 (2021). CAS  PubMed 


PubMed Central  Google Scholar  * Iqbal, M. M., Serralha, M., Kaur, P. & Martino, D. Mapping the landscape of chromatin dynamics during naive CD4+ T-cell activation. _Sci. Rep._ 11,


14101 (2021). CAS  PubMed  PubMed Central  Google Scholar  * Rawlings, J. S., Gatzka, M., Thomas, P. G. & Ihle, J. N. Chromatin condensation via the condensin II complex is required for


peripheral T-cell quiescence. _EMBO J._ 30, 263–276 (2011). CAS  PubMed  Google Scholar  * Evertts, A. G. et al. H4K20 methylation regulates quiescence and chromatin compaction. _Mol. Biol.


Cell_ 24, 3025–3037 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Boonsanay, V. et al. Regulation of skeletal muscle stem cell quiescence by Suv4-20h1-dependent facultative


heterochromatin formation. _Cell Stem Cell_ 18, 229–242 (2016). CAS  PubMed  Google Scholar  * Kieffer-Kwon, K. R. et al. Myc regulates chromatin decompaction and nuclear architecture during


B cell activation. _Mol. Cell_ 67, 566–578.e10 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Bonitto, K., Sarathy, K., Atai, K., Mitra, M. & Coller, H. A. Is there a histone


code for cellular quiescence? _Front. Cell Dev. Biol._ 9, 739780 (2021). PubMed  PubMed Central  Google Scholar  * Willcockson, M. A. et al. H1 histones control the epigenetic landscape by


local chromatin compaction. _Nature_ 589, 293–298 (2021). CAS  PubMed  Google Scholar  * Thurman, R. E. et al. The accessible chromatin landscape of the human genome. _Nature_ 489, 75–82


(2012). CAS  PubMed  PubMed Central  Google Scholar  * Klemm, S. L., Shipony, Z. & Greenleaf, W. J. Chromatin accessibility and the regulatory epigenome. _Nat. Rev. Genet._ 20, 207–220


(2019). CAS  PubMed  Google Scholar  * Consortium, E. P. et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. _Nature_ 583, 699–710 (2020). Google Scholar  *


Stadhouders, R., Filion, G. J. & Graf, T. Transcription factors and 3D genome conformation in cell-fate decisions. _Nature_ 569, 345–354 (2019). CAS  PubMed  Google Scholar  * Cuartero,


S., Stik, G. & Stadhouders, R. Three-dimensional genome organization in immune cell fate and function. _Nat. Rev. Immunol._ 23, 206–221 (2023). CAS  PubMed  Google Scholar  * Dehingia,


B., Milewska, M., Janowski, M. & Pekowska, A. CTCF shapes chromatin structure and gene expression in health and disease. _EMBO Rep._ 23, e55146 (2022). CAS  PubMed  PubMed Central 


Google Scholar  * Takayama, N. et al. The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization. _Cell Stem Cell_


28, 488–501.e10 (2021). CAS  PubMed  Google Scholar  * Kim, T. G. et al. CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice. _Exp. Mol.


Med._ 49, e371 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Brent, M. R. Past roadblocks and new opportunities in transcription factor network mapping. _Trends Genet._ 32, 736–750


(2016). CAS  PubMed  PubMed Central  Google Scholar  * Nowak, J. A. & Fuchs, E. Isolation and culture of epithelial stem cells. _Methods Mol. Biol._ 482, 215–232 (2009). CAS  PubMed 


PubMed Central  Google Scholar  * Liu, L., Cheung, T. H., Charville, G. W. & Rando, T. A. Isolation of skeletal muscle stem cells by fluorescence-activated cell sorting. _Nat. Protoc._


10, 1612–1624 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Machado, L. et al. In situ fixation redefines quiescence and early activation of skeletal muscle stem cells. _Cell Rep._


21, 1982–1993 (2017). CAS  PubMed  Google Scholar  * Nakamura-Ishizu, A., Takizawa, H. & Suda, T. The analysis, roles and regulation of quiescence in hematopoietic stem cells.


_Development_ 141, 4656–4666 (2014). CAS  PubMed  Google Scholar  * Urban, N. & Cheung, T. H. Stem cell quiescence: the challenging path to activation. _Development_ 148, dev165084


(2021). CAS  PubMed  PubMed Central  Google Scholar  * Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. _Nature_ 510, 393–396 (2014).


CAS  PubMed  PubMed Central  Google Scholar  * Li, H. et al. Exploring the dynamics and influencing factors of CD4 T cell activation using single-cell RNA-seq. _iScience_ 26, 107588 (2023).


CAS  PubMed  PubMed Central  Google Scholar  * Guo, X. & Chen, L. From G1 to M: a comparative study of methods for identifying cell cycle phases. _Brief Bioinform._ 25, bbad517 (2024).


PubMed  PubMed Central  Google Scholar  * Hsiao, C. J. et al. Characterizing and inferring quantitative cell cycle phase in single-cell RNA-seq data analysis. _Genome Res._ 30, 611–621


(2020). CAS  PubMed  PubMed Central  Google Scholar  * Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. _Nat. Methods_ 14, 1083–1086 (2017). CAS  PubMed 


PubMed Central  Google Scholar  * Hoang, T. et al. Gene regulatory networks controlling vertebrate retinal regeneration. _Science_ 370, eabb8598 (2020). CAS  PubMed  PubMed Central  Google


Scholar  * Duronio, R. J. & Xiong, Y. Signaling pathways that control cell proliferation. _Cold Spring Harb. Perspect. Biol._ 5, a008904 (2013). PubMed  PubMed Central  Google Scholar  *


Cornwell, J. A. et al. Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal. _Nature_ 619, 363–370 (2023). CAS  PubMed  PubMed Central  Google Scholar  * Cheung, T. H. &


Rando, T. A. Molecular regulation of stem cell quiescence. _Nat. Rev. Mol. Cell Biol._ 14, 329–340 (2013). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was


supported by: grants to H.A.C. from the National Institute of General Medical Sciences (R01 GM081686 and R01 GM0866465), National Institutes of Health (R01 AR070245, 1R01 CA221296-01A1 and


1R01 AR084245-01) National Cancer Institute (RC1 CA147961-02 and P50 CA092131) and Cancer Research Institute (Clinic and Laboratory Integration Program grant), a Melanoma Research Alliance


Team Science Award, a Melanoma Research Foundation Award, the Department of Defense (W81XWH-22-1-0920), an Iris Cantor Women’s Health Center/University of California, Los Angeles (UCLA)


Clinical and Translational Science Institute National Institutes of Health grant (UL1TR000124), the UCLA Specialized Program of Research Excellence in Prostate Cancer (P50 CA092131), the


David Geffen School of Medicine Metabolism Theme, the University of California Cancer Research Coordinating Committee, Broad Stem Cell Research Center Innovation Awards, Rose Hills


Foundation and Hal Gaba awards from the UCLA Broad Stem Cell Research Center, a Jonsson Comprehensive Cancer Center Seed Grant and Leader’s Vision Awards. H.A.C. was a Milton E. Cassel


scholar of the Rita Allen Foundation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los


Angeles, CA, USA Mithun Mitra & Hilary A. Coller * Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA Mithun


Mitra & Hilary A. Coller * Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA Sandra L. Batista * Molecular Biology Institute, University of


California, Los Angeles, Los Angeles, CA, USA Hilary A. Coller Authors * Mithun Mitra View author publications You can also search for this author inPubMed Google Scholar * Sandra L. Batista


View author publications You can also search for this author inPubMed Google Scholar * Hilary A. Coller View author publications You can also search for this author inPubMed Google Scholar


CONTRIBUTIONS M.M. conceived of the idea and design for the manuscript and produced the figures. All of the authors contributed to writing the manuscript. H.A.C. and S.L.B. prepared


Supplementary Tables 1 and 2. M.M. and H.A.C. edited the manuscript. CORRESPONDING AUTHORS Correspondence to Mithun Mitra or Hilary A. Coller. ETHICS DECLARATIONS COMPETING INTERESTS The


authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Cell Biology_ thanks the anonymous reviewers for their contribution to the peer review of this work.


ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION


SUPPLEMENTARY INFORMATION Supplementary Tables 1 and 2. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under


a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such


publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Mitra, M., Batista, S.L. & Coller, H.A. Transcription factor networks in cellular


quiescence. _Nat Cell Biol_ 27, 14–27 (2025). https://doi.org/10.1038/s41556-024-01582-w Download citation * Received: 13 August 2024 * Accepted: 25 November 2024 * Published: 09 January


2025 * Issue Date: January 2025 * DOI: https://doi.org/10.1038/s41556-024-01582-w SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable


link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative