Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling

Mullen, Alan C.; Orlando, David A.; Newman, Jamie J.; Lovén, Jakob; Kumar, R.; Bilodeau, Steve; Reddy, Josina C.; Guenther, Matthew G.; DeKoter, Rodney P.; Young, Richard A.

doi:10.1016/j.cell.2011.08.050

Cited by 534 publications

(580 citation statements)

References 69 publications

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“…For example, although active in many tissues, Hox TFs regulate certain genes specifically in some tissues but not in others (Pearson et al 2005). This is even more pronounced for field-specific selector genes such as scalloped (sd) (Guss et al 2001) or TFs downstream from signaling pathways, most of which are reused throughout development and regulate different genes in different contexts (Barolo and Posakony 2002;Mullen et al 2011;Trompouki et al 2011).…”

mentioning

confidence: 99%

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis-regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict contextspecific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes (cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue-and cell-type-specific TF binding studies.

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confidence: 99%

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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“…The combination of inhibitors in 2i and 3i culture mediums, which act on some specific genes from the Wnt/β‐catenin signaling pathway, promote pluripotency in mESCs through the stabilization of β‐catenin that override the inhibitory effect of Tcf3 on some important pluripotency regulators, such as Oct4 and Nanog 50, 51. The TGF‐β/SMAD signaling pathway maintains self‐renewal in mESC through the BMP/SMAD signalling activation of Id family genes 52, while in hESCs is the Activin/Nodal/SMAD2/3 cascade the one responsible for promoting pluripotency 53. Interestingly, several studies have demonstrated that pluripotency regulators form intricate circuits at the transcriptional level 13, 36, 53, 54, and many of the TFs ( Essrb , Klf4 , Stat3 , Tcf3 ) in these regulatory motifs are downstream effectors of the signaling pathways regulating self‐renewal and differentiation.…”

Section: Pluripotent State Gene Expression Heterogeneity Is Tightly Rmentioning

confidence: 99%

“…The TGF‐β/SMAD signaling pathway maintains self‐renewal in mESC through the BMP/SMAD signalling activation of Id family genes 52, while in hESCs is the Activin/Nodal/SMAD2/3 cascade the one responsible for promoting pluripotency 53. Interestingly, several studies have demonstrated that pluripotency regulators form intricate circuits at the transcriptional level 13, 36, 53, 54, and many of the TFs ( Essrb , Klf4 , Stat3 , Tcf3 ) in these regulatory motifs are downstream effectors of the signaling pathways regulating self‐renewal and differentiation. Although the complete spectrum of signaling pathways regulating pluripotency has not been fully described 55, these results demonstrate the confluence of different environmental signals from the microenvironment for the regulation of pluripotency.…”

Section: Pluripotent State Gene Expression Heterogeneity Is Tightly Rmentioning

confidence: 99%

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Angarica

Sol

2016

BioEssays

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Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine.

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“…In addition to this canonical TGFb signaling pathway, the TGFb receptor complex converges on several other cellular signaling pathways [22,23]. Recently, ChIP-Seq studies indicate that SMAD3 co-occupies genomic loci with transcription factors that are master regulators of diverse cell types including Oct4 in ES cells, MyoD1 in myotubes and Pu.1 in the B-cell lineage [24] and may explain the cellular context-specific effects of TGFb. TGFb is also known for its regulation of postnatal mammary gland development and for its prominent role to act as a tumor suppressor by preventing mammary epithelial cell proliferation [25].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

DeCastro¹,

Cherukuri²,

DiRenzo³

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE December 2012 REPORT TYPE Annual Summary DATES COVERED 15November2011-14November2012 TITLE AND SUBTITLE Regulation of Mammary Stem Cell Quiescence via Post-Translational 5a. CONTRACT NUMBERModification of DeltaNp63alpha. 5b. GRANT NUMBERW81XWH-11-1-0043 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Andrew. J DeCastro, B.S., Pratima Cherukuri, M.S., James DiRenzo, PhD.5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: Andrew.J.DeCastro@Dartmouth.edu 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERDartmouth College, Hanover, NH 03755 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis document is the Annual Summary Report on the training grant awarded to Andrew DeCastro entitled Regulation of Mammary Stem Cell Quiescence via Post-translational Modification of ∆NP63α. Here, we report our findings of the effects of TGFβ (previously validated as a kinase in our kinome screen) mediated phosphorylation of ∆NP63α on stem cell behavior and mitotic activity. Task 1 aims to determine the effects of wild-type, phospho-ablative and phospho-mimetic alleles of ∆NP63α phosphorylation on stem cell behavior in vitro. Thus far, we demonstrate that stem cell enriched populations, as indicated by ALDH1 activity, contain higher concentrations of ∆NP63α mRNA. In addition, we demonstrate that the anti-clonogenic effects of TGFβ are mediated through phosphorylation of ∆NP63α, which is rescued via ectopic expression of the phospho-ablative mutant ∆NP63α-AA. Task 2 aims to identify putative ∆NP63α-kinases and determine their role in mitotic activation. Here we further characterize TGFβ-mediated phosphorylation of ∆NP63α. We demonstrate that TGFβ phosphorylation of ∆NP63α is a destabilizing event, and dependent on the proteasomal degradation pathway. We also report a non-canonical pathway in which ALK5 (TGF...

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Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling

Cited by 534 publications

References 69 publications

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

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