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Directed transdifferentiation of mouse mesoderm to
% E& l! _! n0 x) _0 F/ b4 sheart tissue by defined factors
7 Q# M2 ?8 @& }; u& m; ^Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3
$ n( A4 `1 M1 x" zHeart disease is the leading cause of mortality and morbidity in the3 v% c" y9 B5 N1 N7 V9 |4 j8 \
western world. The heart has little regenerative capacity after. N0 g& \1 m4 v8 T: |
damage, leading to much interest in understanding the factors
8 c ]' e' Y& l( B# q* p: u. erequired to produce new cardiac myocytes. Despite a robust( z6 \4 g' o4 a! V6 p
understanding of the molecular networks regulating cardiac8 c7 B, X! j/ V' `; n- Y
differentiation1,2, no single transcription factor or combination
; M% b+ p; t/ _' s! C+ e2 Dof factors has been shown to activate the cardiac gene program
, y, T6 z9 d3 A6 |7 p' e* wde novo in mammalian cells or tissues. Here we define the minimal: p/ z( j7 w( n7 n5 w! u
requirements for transdifferentiation of mouse mesoderm to7 x" T2 X+ `, [
cardiac myocytes. We show that two cardiac transcription factors,
6 |/ B; [$ U) j; ?; `Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatinremodelling7 O* k1 F5 ]2 m! n! S, _/ {
complexes, Baf60c (also called Smarcd3), can direct- X% F9 f4 F- ^7 A4 d
ectopic differentiation of mouse mesoderm into beating cardiomyocytes,
! l: _0 }2 Z- Qincluding the normally non-cardiogenic posterior
3 |+ e2 d& s |mesoderm and the extraembryonic mesoderm of the amnion.
* A. u$ a/ s- | s( E+ D, KGata4 with Baf60c initiated ectopic cardiac gene expression.
8 f7 J3 P# f7 h( SAddition of Tbx5 allowed differentiation into contracting cardiomyocytes+ k% v$ _# t/ H, @2 z: q
and repression of non-cardiac mesodermal genes.
3 c3 \" c& u, XBaf60c was essential for the ectopic cardiogenic activity of Gata43 [, R: T7 E+ l! L- `* w
and Tbx5, partly by permitting binding of Gata4 to cardiac genes,0 x; ~* S7 P9 e
indicating a novel instructive role for BAF complexes in tissuespecific* p& P" o5 K6 p; g) G) f5 U1 A
regulation. The combined function of these factors establishes3 |6 [, [: A' @
a robust mechanism for controlling cellular differentiation,
# ?9 B7 w8 f1 N% G2 n) u( |9 Yand may allow reprogramming of new cardiomyocytes for regenerative
5 g$ v/ ^* p. s9 Upurpose |
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发表于 2010-5-6 23:27
