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- 积分
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Directed transdifferentiation of mouse mesoderm to6 k% o$ b* V& O0 L+ U' }
heart tissue by defined factors+ K6 y' ?1 I/ Q* P7 m5 S
Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3- e; n7 b0 X. b6 P/ n8 a6 ~, r5 C
Heart disease is the leading cause of mortality and morbidity in the0 k7 X: _+ S8 K7 W' s
western world. The heart has little regenerative capacity after2 z8 J/ N& ^* z
damage, leading to much interest in understanding the factors
5 g$ L" J" @3 v4 Rrequired to produce new cardiac myocytes. Despite a robust
- ^% l5 u( j% p) cunderstanding of the molecular networks regulating cardiac
! `# i# p: _6 ]% V4 X ]differentiation1,2, no single transcription factor or combination; e( O; u8 \$ Y1 q# w+ \
of factors has been shown to activate the cardiac gene program
' L: V$ R q% Y/ h! q4 Nde novo in mammalian cells or tissues. Here we define the minimal% D- V7 L6 q" ]& v! t3 w% a' n6 a. {
requirements for transdifferentiation of mouse mesoderm to+ Q( `& G6 N6 z4 J% e
cardiac myocytes. We show that two cardiac transcription factors,
) P3 m! {5 i% E1 m0 v- L; f2 oGata4 and Tbx5, and a cardiac-specific subunit of BAF chromatinremodelling, j; o9 D6 G( ]" y" g/ X% n C
complexes, Baf60c (also called Smarcd3), can direct
, h- U7 B& m M9 @' vectopic differentiation of mouse mesoderm into beating cardiomyocytes,
, |' K+ W5 b9 q& dincluding the normally non-cardiogenic posterior; f: r+ R. a7 x2 v) q- C$ y" K3 f
mesoderm and the extraembryonic mesoderm of the amnion.3 |. J: w4 U6 @- O3 D" m
Gata4 with Baf60c initiated ectopic cardiac gene expression.
' r, @6 w+ X, X/ l- {1 s: g' [+ oAddition of Tbx5 allowed differentiation into contracting cardiomyocytes# O8 X) F5 B" U" X, W
and repression of non-cardiac mesodermal genes.1 y. \. M; `& p: L( u
Baf60c was essential for the ectopic cardiogenic activity of Gata4: }- d* z5 D' p' d) A8 Z% c! ^
and Tbx5, partly by permitting binding of Gata4 to cardiac genes,
& P/ l. Z1 t6 r1 f" Uindicating a novel instructive role for BAF complexes in tissuespecific
! g1 p+ i6 N/ D, }regulation. The combined function of these factors establishes
% D9 U, }+ E; @/ Y$ oa robust mechanism for controlling cellular differentiation,
3 a* t8 ~% ~7 I9 n# Vand may allow reprogramming of new cardiomyocytes for regenerative7 K) N7 a7 e% B
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发表于 2010-5-6 23:27
