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Directed transdifferentiation of mouse mesoderm to
1 F0 z$ L+ X rheart tissue by defined factors9 s& v8 F9 a+ W, B2 _8 T" `
Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3, f9 R) D5 ?7 B5 U+ h, b3 U
Heart disease is the leading cause of mortality and morbidity in the& z9 o- D+ n8 \" E+ j' }
western world. The heart has little regenerative capacity after3 U; ]$ l1 l. `2 B) g
damage, leading to much interest in understanding the factors
" c, N) A% z: ^3 ^1 X9 H8 a( Crequired to produce new cardiac myocytes. Despite a robust$ z) C) M: a0 K4 H U1 G
understanding of the molecular networks regulating cardiac
' p, V; d t" j" P4 Cdifferentiation1,2, no single transcription factor or combination, |* b% `! X2 k3 Z, H
of factors has been shown to activate the cardiac gene program" O" l: a: ]1 X" I: d b
de novo in mammalian cells or tissues. Here we define the minimal' `& O% H w9 H7 k
requirements for transdifferentiation of mouse mesoderm to
3 L+ b$ G$ a$ X1 Hcardiac myocytes. We show that two cardiac transcription factors,1 M8 b/ U( z5 B/ F/ g
Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatinremodelling" R* V- i1 m, T9 q
complexes, Baf60c (also called Smarcd3), can direct
6 x3 o5 C$ `' E+ o1 Vectopic differentiation of mouse mesoderm into beating cardiomyocytes,% A$ y8 D' p* v! d( V) K
including the normally non-cardiogenic posterior
! p6 a2 z$ Z9 r nmesoderm and the extraembryonic mesoderm of the amnion.: Z$ j: E( Z2 x7 j+ G" m2 _0 t, w
Gata4 with Baf60c initiated ectopic cardiac gene expression.5 w q& u! b1 h9 b
Addition of Tbx5 allowed differentiation into contracting cardiomyocytes" s1 k$ e/ d/ `7 Z
and repression of non-cardiac mesodermal genes." C5 a! i$ W! p
Baf60c was essential for the ectopic cardiogenic activity of Gata4# B! ?' D* X) \0 ], }' P8 h6 \7 m
and Tbx5, partly by permitting binding of Gata4 to cardiac genes,
* N* r2 j. J) Z/ k' f4 |( }indicating a novel instructive role for BAF complexes in tissuespecific! q2 H, e3 Y4 V1 m# c d1 B
regulation. The combined function of these factors establishes5 _6 U" P7 D M/ @* Z0 Z0 V8 s1 f
a robust mechanism for controlling cellular differentiation,
9 D; C) K$ X, ]6 S- i' ^and may allow reprogramming of new cardiomyocytes for regenerative
3 k- h* I" m6 P/ h% gpurpose |
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发表于 2010-5-6 23:27
