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Directed transdifferentiation of mouse mesoderm to
" Z, [+ y/ L/ ~* _: Z5 fheart tissue by defined factors/ x* N( a+ Q# h# e. P( F
Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3. j. G) G' c3 m) k' i
Heart disease is the leading cause of mortality and morbidity in the4 a+ L; }% R9 Q0 m/ {" v
western world. The heart has little regenerative capacity after
: U u! L/ c* C$ ?- U- ndamage, leading to much interest in understanding the factors
$ ^. ` }5 O- \ C6 M1 `required to produce new cardiac myocytes. Despite a robust
2 P8 w( H1 a- [) u8 M$ B# Iunderstanding of the molecular networks regulating cardiac1 `( ~( Q* l4 Z) v4 _5 }
differentiation1,2, no single transcription factor or combination
4 G/ b% p C, O2 o+ }5 n; I: }of factors has been shown to activate the cardiac gene program4 }$ [* i' \3 ^1 S. c
de novo in mammalian cells or tissues. Here we define the minimal$ o- S$ J* ?8 B0 ?) p, x: F
requirements for transdifferentiation of mouse mesoderm to
9 Y. H% F8 |2 q% ccardiac myocytes. We show that two cardiac transcription factors,5 A; ~1 J4 X1 @& Y; ~
Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatinremodelling
, H+ m4 B- S$ h" f2 L0 A+ acomplexes, Baf60c (also called Smarcd3), can direct& B3 V/ G. Q$ e* u% \
ectopic differentiation of mouse mesoderm into beating cardiomyocytes,, _3 w( [3 x6 r, d! v
including the normally non-cardiogenic posterior8 v% Z7 P% [( v$ d( l1 L+ Z
mesoderm and the extraembryonic mesoderm of the amnion.6 j. f+ P1 f4 i/ K7 z
Gata4 with Baf60c initiated ectopic cardiac gene expression.
`2 ?% {3 x) \ y4 L! R/ TAddition of Tbx5 allowed differentiation into contracting cardiomyocytes
; Y7 e# B5 b# ~; ?and repression of non-cardiac mesodermal genes.; b3 }8 p* ~- G8 |7 b& R
Baf60c was essential for the ectopic cardiogenic activity of Gata4
( v2 v- B1 S8 Fand Tbx5, partly by permitting binding of Gata4 to cardiac genes,
) G5 Q- S9 C2 V) d, r7 Aindicating a novel instructive role for BAF complexes in tissuespecific* W5 z) i5 S; S
regulation. The combined function of these factors establishes
Y5 N9 o% I5 G, T( ia robust mechanism for controlling cellular differentiation,
) \2 r) @( w0 K1 f. ]# x, n/ l3 wand may allow reprogramming of new cardiomyocytes for regenerative1 K5 K7 w: X* U5 h% j, j: R
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发表于 2010-5-6 23:27
