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Directed transdifferentiation of mouse mesoderm to1 ^' ? L. S, [7 g2 p$ j$ l
heart tissue by defined factors9 f5 B w9 D. I2 @4 q
Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3
7 X9 X: X6 D8 z3 b& UHeart disease is the leading cause of mortality and morbidity in the
5 o: w, @" D' Ewestern world. The heart has little regenerative capacity after
5 k+ Y' e3 U) _7 Fdamage, leading to much interest in understanding the factors
6 J5 H; I' f7 P, G% U! H' M* D% Mrequired to produce new cardiac myocytes. Despite a robust
, o4 ~: C5 ^% p- ^0 n& Vunderstanding of the molecular networks regulating cardiac
+ j. \; k2 x1 i& Tdifferentiation1,2, no single transcription factor or combination) T h7 N: k, ?9 b) Q
of factors has been shown to activate the cardiac gene program2 a3 C5 B `* O' S0 _, ~( s+ b
de novo in mammalian cells or tissues. Here we define the minimal) J% Y4 Q' M3 H, j) e4 W
requirements for transdifferentiation of mouse mesoderm to+ [, T2 v) D; E& l7 I# x2 z
cardiac myocytes. We show that two cardiac transcription factors,* [. a: Y5 ]% g2 ]& h1 M% m- A7 {9 K
Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatinremodelling
, G' `6 f: u) n0 W& @7 K- ucomplexes, Baf60c (also called Smarcd3), can direct
4 U9 n T6 H1 Z; D9 zectopic differentiation of mouse mesoderm into beating cardiomyocytes,% A3 t5 w1 B9 I
including the normally non-cardiogenic posterior
1 R; p6 D( O: pmesoderm and the extraembryonic mesoderm of the amnion.$ O) D* J) c4 d$ j
Gata4 with Baf60c initiated ectopic cardiac gene expression.
, m- }; h y0 Z* o/ A" A4 Y- |5 sAddition of Tbx5 allowed differentiation into contracting cardiomyocytes
1 C# ?. i P8 e# i" Y/ }1 Oand repression of non-cardiac mesodermal genes.
/ D0 l0 }# b5 q# ABaf60c was essential for the ectopic cardiogenic activity of Gata4! P. z0 }1 c) x; T2 _, T: Q$ w' |
and Tbx5, partly by permitting binding of Gata4 to cardiac genes,$ O5 G" S# A E# q* ] [' W
indicating a novel instructive role for BAF complexes in tissuespecific H6 d& S: p1 I, _
regulation. The combined function of these factors establishes7 l, {& d- z* ^' d# [
a robust mechanism for controlling cellular differentiation,
( F( A; J, h0 W8 ? ?and may allow reprogramming of new cardiomyocytes for regenerative
8 Q1 J4 ~- f$ g! ~0 ^( @purpose |
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发表于 2010-5-6 23:27
