A Single Element Maintains Repression of the Key Developmental Regulator

English version České info

In development, lineage-restricted transcription factors simultaneously promote differentiation while repressing alternative fates. Molecular dissection of this process has been challenging as transcription factor loci are regulated by many trans-acting factors functioning through dispersed cis elements. It is not understood whether these elements function collectively to confer transcriptional regulation, or individually to control specific aspects of activation or repression, such as initiation versus maintenance. Here, we have analyzed cis element regulation of the critical hematopoietic factor Gata2, which is expressed in early precursors and repressed as GATA-1 levels rise during terminal differentiation. We engineered mice lacking a single cis element −1.8 kb upstream of the Gata2 transcriptional start site. Although Gata2 is normally repressed in late-stage erythroblasts, the −1.8 kb mutation unexpectedly resulted in reactivated Gata2 transcription, blocked differentiation, and an aberrant lineage-specific gene expression pattern. Our findings demonstrate that the −1.8 kb site selectively maintains repression, confers a specific histone modification pattern and expels RNA Polymerase II from the locus. These studies reveal how an individual cis element establishes a normal developmental program via regulating specific steps in the mechanism by which a critical transcription factor is repressed.

Vyšlo v časopise: A Single Element Maintains Repression of the Key Developmental Regulator. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001103
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001103

Souhrn

Zdroje

1. ArnoneMI

DavidsonEH

1997 The hardwiring of development: organization and function of genomic regulatory systems. Development 124 1851 1864

2. SonejiS

HuangS

LooseM

DonaldsonIJ

PatientR

2007 Inference, validation, and dynamic modeling of transcription networks in multipotent hematopoietic cells. Ann N Y Acad Sci 1106 30 40

3. StrahlBD

AllisCD

2000 The language of covalent histone modifications. Nature 403 41 45

4. MohnF

SchubelerD

2009 Genetics and epigenetics: stability and plasticity during cellular differentiation. Trends Genet 25 129 136

5. BurchJB

2005 Regulation of GATA gene expression during vertebrate development. Semin Cell Dev Biol 16 71 81

6. BresnickEH

MartowiczML

PalS

JohnsonKD

2005 Developmental control via GATA factor interplay at chromatin domains. J Cell Physiol 205 1 9

7. KanekoH

ShimizuR

YamamotoM.

GATA factor switching during erythroid differentiation. Curr Opin Hematol 17 163 168

8. TsaiFY

OrkinSH

1997 Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89 3636 3643

9. TsaiFY

KellerG

KuoFC

WeissM

ChenJ

1994 An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371 221 226

10. FujiwaraY

BrowneCP

CunniffK

GoffSC

OrkinSH

1996 Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci U S A 93 12355 12358

11. TingCN

OlsonMC

BartonKP

LeidenJM

1996 Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384 474 478

12. BriegelK

LimKC

PlankC

BeugH

EngelJD

1993 Ectopic expression of a conditional GATA-2/estrogen receptor chimera arrests erythroid differentiation in a hormone-dependent manner. Genes Dev 7 1097 1109

13. PersonsDA

AllayJA

AllayER

AshmunRA

OrlicD

1999 Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. Blood 93 488 499

14. HeyworthC

GaleK

DexterM

MayG

EnverT

1999 A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal. Genes Dev 13 1847 1860

15. FujiwaraT

O'GeenH

KelesS

BlahnikK

LinnemannAK

2009 Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Mol Cell 36 667 681

16. WozniakRJ

BresnickEH

2008 Epigenetic control of complex loci during erythropoiesis. Curr Top Dev Biol 82 55 83

17. GrassJA

BoyerME

PalS

WuJ

WeissMJ

2003 GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc Natl Acad Sci U S A 100 8811 8816

18. PalS

CantorAB

JohnsonKD

MoranTB

BoyerME

2004 Coregulator-dependent facilitation of chromatin occupancy by GATA-1. Proc Natl Acad Sci U S A 101 980 985

19. MartowiczML

GrassJA

BoyerME

GuendH

BresnickEH

2005 Dynamic GATA factor interplay at a multicomponent regulatory region of the GATA-2 locus. J Biol Chem 280 1724 1732

20. MartowiczML

GrassJA

BresnickEH

2006 GATA-1-mediated transcriptional repression yields persistent transcription factor IIB-chromatin complexes. J Biol Chem 281 37345 37352

21. GrassJA

JingH

KimSI

MartowiczML

PalS

2006 Distinct functions of dispersed GATA factor complexes at an endogenous gene locus. Mol Cell Biol 26 7056 7067

22. WangH

ZhangY

ChengY

ZhouY

KingDC

2006 Experimental validation of predicted mammalian erythroid cis-regulatory modules. Genome Res 16 1480 1492

23. Kobayashi-OsakiM

OhnedaO

SuzukiN

MinegishiN

YokomizoT

2005 GATA motifs regulate early hematopoietic lineage-specific expression of the Gata2 gene. Mol Cell Biol 25 7005 7020

24. PimandaJE

OttersbachK

KnezevicK

KinstonS

ChanWY

2007 Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proc Natl Acad Sci U S A 104 17692 17697

25. WozniakRJ

BoyerME

GrassJA

LeeY

BresnickEH

2007 Context-dependent GATA factor function: combinatorial requirements for transcriptional control in hematopoietic and endothelial cells. J Biol Chem 282 14665 14674

26. ZhangJ

SocolovskyM

GrossAW

LodishHF

2003 Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 102 3938 3946

27. SocolovskyM

NamH

FlemingMD

HaaseVH

BrugnaraC

2001 Ineffective erythropoiesis in Stat5a(−/−)5b(−/−) mice due to decreased survival of early erythroblasts. Blood 98 3261 3273

28. PalisJ

2008 Ontogeny of erythropoiesis. Curr Opin Hematol 15 155 161

29. McGrathK

PalisJ

2008 Ontogeny of erythropoiesis in the mammalian embryo. Curr Top Dev Biol 82 1 22

30. LenoxLE

PerryJM

PaulsonRF

2005 BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 105 2741 2748

31. PerryJM

HarandiOF

PaulsonRF

2007 BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood 109 4494 4502

32. PorayetteP

PaulsonRF

2008 BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development. Dev Biol 317 24 35

33. MinegishiN

OhtaJ

SuwabeN

NakauchiH

IshiharaH

1998 Alternative promoters regulate transcription of the mouse GATA-2 gene. J Biol Chem 273 3625 3634

34. YuM

RivaL

XieH

SchindlerY

MoranTB

2009 Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis. Mol Cell 36 682 695

35. ShilatifardA

2008 Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol 20 341 348

36. PinskayaM

MorillonA

2009 Histone H3 lysine 4 di-methylation: a novel mark for transcriptional fidelity? Epigenetics 4 302 306

37. HublitzP

AlbertM

PetersAH

2009 Mechanisms of transcriptional repression by histone lysine methylation. Int J Dev Biol 53 335 354

38. BarskiA

CuddapahS

CuiK

RohTY

SchonesDE

2007 High-resolution profiling of histone methylations in the human genome. Cell 129 823 837

39. ZhaoXD

HanX

ChewJL

LiuJ

ChiuKP

2007 Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1 286 298

40. CuiK

ZangC

RohTY

SchonesDE

ChildsRW

2009 Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4 80 93

41. IllingworthRS

BirdAP

2009 CpG islands–‘a rough guide’. FEBS Lett 583 1713 1720

42. SongF

SmithJF

KimuraMT

MorrowAD

MatsuyamaT

2005 Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci U S A 102 3336 3341

43. IrizarryRA

Ladd-AcostaC

WenB

WuZ

MontanoC

2009 The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41 178 186

44. OrfordK

KharchenkoP

LaiW

DaoMC

WorhunskyDJ

2008 Differential H3K4 methylation identifies developmentally poised hematopoietic genes. Dev Cell 14 798 809

45. SchuettengruberB

ChourroutD

VervoortM

LeblancB

CavalliG

2007 Genome regulation by polycomb and trithorax proteins. Cell 128 735 745

46. BlobelGA

NakajimaT

EcknerR

MontminyM

OrkinSH

1998 CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. Proc Natl Acad Sci U S A 95 2061 2066

47. HongW

NakazawaM

ChenYY

KoriR

VakocCR

2005 FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1. Embo J 24 2367 2378

48. RodriguezP

BonteE

KrijgsveldJ

KolodziejKE

GuyotB

2005 GATA-1 forms distinct activating and repressive complexes in erythroid cells. Embo J 24 2354 2366

49. SnowJW

OrkinSH

2009 Translational isoforms of FOG1 regulate GATA1-interacting complexes. J Biol Chem 284 29310 29319

50. KimSI

BultmanSJ

KieferCM

DeanA

BresnickEH

2009 BRG1 requirement for long-range interaction of a locus control region with a downstream promoter. Proc Natl Acad Sci U S A 106 2259 2264

51. ImH

GrassJA

JohnsonKD

KimSI

BoyerME

2005 Chromatin domain activation via GATA-1 utilization of a small subset of dispersed GATA motifs within a broad chromosomal region. Proc Natl Acad Sci U S A 102 17065 17070

52. ImH

GrassJA

JohnsonKD

BoyerME

WuJ

2004 Measurement of protein-DNA interactions in vivo by chromatin immunoprecipitation. Methods Mol Biol 284 129 146