Transcriptional Competence and the Active Marking of Tissue-specific Enhancers by Defined Transcription Factors in Embryonic and Induced Pluripotent Stem Cells

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2009 Dec 17

PMID 20008934

Citations 105

Authors

Jian Xu

Jason A Watts

Scott D Pope

Paul Gadue

Mark Kamps

Kathrin Plath

Kenneth S Zaret

Stephen T Smale

Affiliations

Soon will be listed here.

Abstract

We reported previously that well-characterized enhancers but not promoters for typical tissue-specific genes, including the classic Alb1 gene, contain unmethylated CpG dinucleotides and evidence of pioneer factor interactions in embryonic stem (ES) cells. These properties, which are distinct from the bivalent histone modification domains that characterize the promoters of genes involved in developmental decisions, raise the possibility that genes expressed only in differentiated cells may need to be marked at the pluripotent stage. Here, we demonstrate that the forkhead family member FoxD3 is essential for the unmethylated mark observed at the Alb1 enhancer in ES cells, with FoxA1 replacing FoxD3 following differentiation into endoderm. Up-regulation of FoxD3 and loss of CpG methylation at the Alb1 enhancer accompanied the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. Studies of two genes expressed in specific hematopoietic lineages revealed that the establishment of enhancer marks in ES cells and iPS cells can be regulated both positively and negatively. Furthermore, the absence of a pre-established mark consistently resulted in resistance to transcriptional activation in the repressive chromatin environment that characterizes differentiated cells. These results support the hypothesis that pluripotency and successful reprogramming may be critically dependent on the marking of enhancers for many or all tissue-specific genes.

Citing Articles

Foxa deficiency restricts hepatitis B virus biosynthesis through epigenic silencing.

Matrenec R, Oropeza C, Dekoven E, Matrenec C, Maienschein-Cline M, Chau C J Virol. 2024; 98(11):e0137124.

PMID: 39377604 PMC: 11575325. DOI: 10.1128/jvi.01371-24.

RUNX1 C-terminal mutations impair blood cell differentiation by perturbing specific enhancer-promoter networks.

Jayne N, Liang Z, Lim D, Chen P, Diaz C, Arimoto K Blood Adv. 2024; 8(10):2410-2423.

PMID: 38513139 PMC: 11112616. DOI: 10.1182/bloodadvances.2023011484.

Molecular Basis of Cell Reprogramming into iPSCs with Exogenous Transcription Factors.

Kondoh H Results Probl Cell Differ. 2024; 72:193-218.

PMID: 38509259 DOI: 10.1007/978-3-031-39027-2_11.

vignettes.

Zaret K Genes Dev. 2023; 37(1-2):63-68.

PMID: 37061958 PMC: 10046443. DOI: 10.1101/gad.350444.123.

A gene regulatory network for neural induction.

Trevers K, Lu H, Yang Y, Thiery A, Strobl A, Anderson C Elife. 2023; 12.

PMID: 36867045 PMC: 10038663. DOI: 10.7554/eLife.73189.

References

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View

Bernstein B, Mikkelsen T, Xie X, Kamal M, Huebert D, Cuff J . A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125(2):315-26. DOI: 10.1016/j.cell.2006.02.041. View

Forrester W, Fernandez L, Grosschedl R . Nuclear matrix attachment regions antagonize methylation-dependent repression of long-range enhancer-promoter interactions. Genes Dev. 1999; 13(22):3003-14. PMC: 317154. DOI: 10.1101/gad.13.22.3003. View

Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason M, Heidersbach A . Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature. 2009; 460(7257):863-8. PMC: 3891576. DOI: 10.1038/nature08212. View

Clevidence D, Overdier D, Tao W, Qian X, Pani L, Lai E . Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. Proc Natl Acad Sci U S A. 1993; 90(9):3948-52. PMC: 46423. DOI: 10.1073/pnas.90.9.3948. View

Gadue P, Gouon-Evans V, Cheng X, Wandzioch E, Zaret K, Grompe M . Generation of monoclonal antibodies specific for cell surface molecules expressed on early mouse endoderm. Stem Cells. 2009; 27(9):2103-13. PMC: 2890285. DOI: 10.1002/stem.147. View

Denslow S, Wade P . The human Mi-2/NuRD complex and gene regulation. Oncogene. 2007; 26(37):5433-8. DOI: 10.1038/sj.onc.1210611. View

Zhou L, Nazarian A, Smale S . Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway. Mol Cell Biol. 2004; 24(6):2385-96. PMC: 355839. DOI: 10.1128/MCB.24.6.2385-2396.2004. View

Xu J, Pope S, Jazirehi A, Attema J, Papathanasiou P, Watts J . Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells. Proc Natl Acad Sci U S A. 2007; 104(30):12377-82. PMC: 1941477. DOI: 10.1073/pnas.0704579104. View

10.

Zhou L, Nazarian A, Xu J, Tantin D, Corcoran L, Smale S . An inducible enhancer required for Il12b promoter activity in an insulated chromatin environment. Mol Cell Biol. 2007; 27(7):2698-712. PMC: 1899891. DOI: 10.1128/MCB.00788-06. View

11.

Gualdi R, Bossard P, Zheng M, Hamada Y, Coleman J, Zaret K . Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 1996; 10(13):1670-82. DOI: 10.1101/gad.10.13.1670. View

12.

Gadue P, Huber T, Paddison P, Keller G . Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci U S A. 2006; 103(45):16806-11. PMC: 1636536. DOI: 10.1073/pnas.0603916103. View

13.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

14.

Brandeis M, Frank D, Keshet I, Siegfried Z, Mendelsohn M, Nemes A . Sp1 elements protect a CpG island from de novo methylation. Nature. 1994; 371(6496):435-8. DOI: 10.1038/371435a0. View

15.

Keller G, Kennedy M, Papayannopoulou T, Wiles M . Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol. 1993; 13(1):473-86. PMC: 358927. DOI: 10.1128/mcb.13.1.473-486.1993. View

16.

MacLeod D, Charlton J, Mullins J, Bird A . Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. Genes Dev. 1994; 8(19):2282-92. DOI: 10.1101/gad.8.19.2282. View

17.

Ramirez-Carrozzi V, Nazarian A, Li C, Gore S, Sridharan R, Imbalzano A . Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. Genes Dev. 2006; 20(3):282-96. PMC: 1361700. DOI: 10.1101/gad.1383206. View

18.

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

19.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

20.

Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K . Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2008; 1(1):55-70. DOI: 10.1016/j.stem.2007.05.014. View