WNT signaling promotes Nkx2.5 expression and early cardiomyogenesis via downregulation of Hdac1

Liu, Zhiqiang; Li, Tao; Liu, Yinan; Jia, Zhonghua; Liu, Yanming; Zhang, Chenguang; Chen, Ping; Ma, Kangtao; Affara, Nabeel A.; Zhou, Chen

doi:10.1016/j.bbamcr.2008.08.013

Cited by 77 publications

(76 citation statements)

References 37 publications

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“…We find that Wnt signaling promotes Nkx2-5, Isl1, and Baf60c. That Wnt controls Nkx2-5 has been noted previously, and it has been suggested that this control is mediated by a down-regulation of HDAC1 (15). Several effects of Bmp signaling in cardiomyocyte differentiation have been described previously High Bmp activity is required for Gata4 expression and for the initiation of Nkx2-5 expression at E8, but our data indicate that at E9 the maintenance of Nkx2-5 no longer is Bmp dependent (9,13,14).…”

Section: Discussioncontrasting

confidence: 53%

“…Studies in mouse, chick, frog, and fish demonstrate that high levels of Bmp activity are necessary for the expression of Nkx2-5 and Gata4 and for myocardial differentiation (5,9,13,14). Canonical Wnt signals are essential for proliferation of Isl1-expressing SHF progenitors and also promote Nkx2-5 expression and subsequent cardiac differentiation by down-regulating HDAC1 (5,13,15). In the presence of canonical Wnt ligands, β-catenin is stabilized and translocates to the nucleus, where it interacts with Lef/Tcf transcription factors to activate target genes (16)(17)(18).…”

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confidence: 99%

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Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Klaus

Müller²,

Schulz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Progenitor cells of the first and second heart fields depend on cardiac-specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiacspecific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/β-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/β-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development.cardiogenesis | MesP1-cre | mesoderm patterning | canonical Wnt | progenitor differentiation in culture

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Section: Discussioncontrasting

confidence: 53%

mentioning

confidence: 99%

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Klaus

Müller²,

Schulz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…ES cell pluripotency and cell fate determination are profoundly affected by MAPK, Wnt, and TGFβ signaling pathways (45). It is interesting to note therefore that HDAC1 and -2 have been shown to be downstream effectors of Wnt signaling during cardiomyocyte (13) and oligodendrocyte (46) differentiation. A more prudent application of our system using defined (serum-free) media, over prolonged periods, is currently underway to decipher the roles of HDAC1 and -2 in lineage-specific differentiation programs.…”

Section: Hdac1 But Not Hdac2 Regulates H3k56ac and Is Required Formentioning

confidence: 99%

“…These data concur with a number of studies in which HDAC inhibitors have been applied to pluripotent cells. Treatment of day 7 EBs with TSA promotes cardiomyocyte differentiation (40), as measured by an increase in Nkx2-5 expression, which may be a direct target of HDAC1 (13).…”

Section: Hdac1 But Not Hdac2 Regulates H3k56ac and Is Required Formentioning

confidence: 99%

“…These complexes are then targeted to chromatin by sequencespecific (often cell-specific) transcription factors to repress transcription in cooperation with other chromatin modifiers, such as the lysine-specific demethylase, LSD1, in the CoREST complex (7)(8)(9). As part of these multiprotein complexes, the activity of HDAC1 and HDAC2 has been implicated in the regulation of cell cycle progression by tumor suppressors (10)(11)(12), differentiation (13,14), cellular aging (15), and cancer (16). Indeed, a variety of HDAC inhibitors that target both HDAC1 and -2 are currently being tested in the clinic as potential anticancer therapeutics (17).…”

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confidence: 99%

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Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation

Dovey

Foster²,

Cowley³

2010

Proc. Natl. Acad. Sci. U.S.A.

261

216

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Histone deacetylases (HDAC) 1 and 2 are highly similar enzymes that help regulate chromatin structure as the core catalytic components of corepressor complexes. Although tissue-specific deletion of HDAC1 and HDAC2 has demonstrated functional redundancy, germ-line deletion of HDAC1 in the mouse causes early embryonic lethality, whereas HDAC2 does not. To address the unique requirement for HDAC1 in early embryogenesis we have generated conditional knockout embryonic stem (ES) cells in which HDAC1 or HDAC2 genes can be inactivated. Deletion of HDAC1, but not HDAC2, causes a significant reduction in the HDAC activity of Sin3A, NuRD, and CoREST corepressor complexes. This reduced corepressor activity results in a specific 1.6-fold increase in histone H3 K56 acetylation (H3K56Ac), thus providing genetic evidence that H3K56Ac is a substrate of HDAC1. In culture, ES cell proliferation was unaffected by loss of either HDAC1 or HDAC2. Rather, we find that loss of HDAC1 affects ES cell differentiation. ES cells lacking either HDAC1 or HDAC2 were capable of forming embryoid bodies (EBs), which stimulates differentiation into the three primary germ layers. However, HDAC1-deficient EBs were significantly smaller, showed spontaneous rhythmic contraction, and increased expression of both cardiomyocyte and neuronal markers. In summary, our genetic study of HDAC1 and HDAC2 in ES cells, which mimic the embryonic epiblast, has identified a unique requirement for HDAC1 in the optimal activity of HDAC1/2 corepressor complexes and cell fate determination during differentiation.corepressor | acetylation | deacetylation | chromatin C lass I histone deacetylases (HDAC1, -2, -3, and -8) are highly conserved enzymes present in the nucleus of all cells, where they help modulate levels of gene expression (1). The best characterized substrates of HDACs are the N-terminal tails of the core histones H2A, H2B, H3 and H4. Deacetylation of histone tails results in a "tightening" of chromatin, due to the electrostatic potential of unacetylated lysine residues to promote internucleosomal interactions (2, 3) and the loss of a binding site for components of the transcriptional machinery containing a bromodomain, e.g., TAFII1 (4).Among the class I HDACs, HDAC1 and HDAC2 are the most similar (83% amino acid identity), sharing an almost identical catalytic core domain and a conserved C-terminal tail (5). In mammalian cells HDAC1 and HDAC2 interact together (6) to form the catalytic core of a number of higher-order complexes including Sin3A, NuRD, CoREST, and NODE (reviewed in ref. 1). These complexes are then targeted to chromatin by sequencespecific (often cell-specific) transcription factors to repress transcription in cooperation with other chromatin modifiers, such as the lysine-specific demethylase, LSD1, in the CoREST complex (7-9). As part of these multiprotein complexes, the activity of HDAC1 and HDAC2 has been implicated in the regulation of cell cycle progression by tumor suppressors (10-12), differentiation (13, 14), cellular aging (15), and c...

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HDACs regulate the differentiation of endothelial cells from human iPSCs

Wang

et al. 2022

Cell Biochemistry & Function

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Human induced pluripotent stem cells (hiPSCs) possess the potential to differentiate toward vascular cells including endothelial cells (ECs), pericytes, and smooth muscle cells. Epigenetic mechanisms including DNA methylation and histone modification play a crucial role in regulating lineage differentiation and specification. Herein, we utilized a three‐stage protocol to induce differentiation of mesoderm, vascular progenitors, and ECs from hiPSCs and investigated the regulatory effects of histone acetylation on the differentiation processes. We found that the expression of several histone deacetylases (HDACs), including HDAC1, HDAC5, and HDAC7, were greatly upregulated at the second stage and downregulated at the third stage. Interestingly, although HDAC1 remained in the nucleus during the EC differentiation, HDAC5 and HDAC7 displayed cytosol/nuclear translocation during the differentiation process. Inhibition of HDACs with sodium butyrate (NaBt) or BML210 could hinder the differentiation of vascular progenitors at the second stage and facilitate EC induction at the third stage. Further investigation revealed that HDAC may modulate the stepwise EC differentiation via regulating the expression of endothelial transcription factors ERG, ETS1, and MEF2C. Opposite to the expression of EC markers, the smooth muscle/pericyte marker ACTA2 was upregulated at the second stage and downregulated at the third stage by NaBt. The stage‐specific regulation of ACTA2 by HDAC inhibition was likely through regulating the expression of TGFβ2 and PDGFB. This study suggests that HDACs play different roles at different stages of EC induction by promoting the commitment of vascular progenitors and impeding the later stage differentiation of ECs.

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WNT signaling promotes Nkx2.5 expression and early cardiomyogenesis via downregulation of Hdac1

Cited by 77 publications

References 37 publications

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation

HDACs regulate the differentiation of endothelial cells from human iPSCs

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