Histone Deacetylase 3 Regulates Smooth Muscle Differentiation in Neural Crest Cells and Development of the Cardiac Outflow Tract

Singh, Nikhil; Trivedi, Chinmay M.; Lu, Minmin; Mullican, Shannon E.; Lazar, Mitchell A.; Epstein, Jonathan A.

doi:10.1161/circresaha.111.255067

Cited by 63 publications

(50 citation statements)

References 44 publications

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“…Hdac3 in NCCs is required to regulate PAA and OFT development; however, its direct target genes are unknown (38). Some histone-modifying enzymes are also known to regulate OFT development, but their cellular sites of actions are undefined.…”

Section: Discussionmentioning

confidence: 99%

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Xiong²,

Shang³

et al. 2013

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

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Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21 cip1 , to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNAbinding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.N eural crest cells (NCCs) originate from the neural crest of the dorsal neural tube and migrate to many regions of the embryo, where they differentiate into a variety of local cells, including cardiovascular tissues (1). NCCs that emigrate from the neural crest of rhombomere 6-8 to pharyngeal arches and the heart are essential for the patterning of pharyngeal arch arteries (PAAs) and the cardiac outflow tract (OFT) (2, 3). These NCCs also differentiate into vascular smooth muscle cells (SMCs) of PAAs and the muscular septum of the aorta and pulmonary trunk (4, 5). In contrast, NCCs from the cephalic neural tube migrate to the face and forebrain to form craniofacial bones, as well as SMCs of facial and forebrain vessels (6). Thus, NCCs are critical for the formation of cardiac OFT and vascular supplies of large areas of the body.Disruption of NCC development, either directly or indirectly, results in many forms of human birth defects with cardiovascular malformations, including Alagille, Carpenter, Ivemark, Leopard, Williams, DiGeorge, and CHARGE syndromes (7). These syndromes involve defects in PAAs or cardiac OFT, such as coarctation of the aorta, interrupted aortic arch, pulmonary artery stenosis, double-outlet right ventricle, tetralogy of Fallot, or persistent truncus arteriosus. During PAA and OFT development, NCCs are regulated by numerous transcription factors, including Pax3, Pbx1/2/3, Tbx1/2/3/20, Msx1/2, Hand2, AP2a, Cited2, Pitx2, Sox4, Foxc1/c2/d3/h1, Fog2, Gata3/4/6, and Notch/NICD (8). Such extensive involvement of transcription factors indicates the importance of gene pr...

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Section: Discussionmentioning

confidence: 99%

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Xiong²,

Shang³

et al. 2013

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

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“…1G). Previously, we demonstrated that neural crest-specific genetic deletion of HDAC3 resulted in anomalous outflow tract septation and distal outflow tract mor- phogenesis; however, outflow tract rotation and semilunar valve development were unaffected (69). Instead, second heart field-derived myocardium at the base of the outflow tract governs the normal outflow tract rotation (70).…”

Section: Myh6komentioning

confidence: 99%

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

Lewandowski

Janardhan

Trivedi

2015

Journal of Biological Chemistry

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Background: Histone-modifying genes play critical roles in the pathogenesis of human congenital heart disease. Results: HDAC3 recruits PRC2 complex to mediate epigenetic silencing of TGF-␤1 in a deacetylase-independent manner within second heart field progenitor cells. Conclusion: HDAC3-mediated epigenetic silencing of TGF-␤1 is required for normal heart development. Significance: This is the first report of HDAC-mediated epigenetic regulation of second heart field development.

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“…For example, Hdac3, a member of the Class I HDAC family, has been implicated in cardiac development and homeostasis (Montgomery et al, 2008;Singh et al, 2011), acting by repressing the expression of Tbx5 in early development (Lewandowski et al, 2014). During development, it is highly expressed in the SAN (Wu et al, 2014), AVN and Purkinje fibres (Risebro et al, 2012).…”

Section: Histone Modifications Mediating Ccs-specific Gene Expressionmentioning

confidence: 99%

The formation and function of the cardiac conduction system

2016

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The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. CCS development involves complex regulatory networks that act in stage-, tissue-and dose-dependent manners, and recent findings indicate that the activity of these networks is sensitive to common genetic variants associated with cardiac arrhythmias. Here, we review how these findings have provided novel insights into the regulatory mechanisms and transcriptional networks underlying CCS formation and function.

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Histone Deacetylase 3 Regulates Smooth Muscle Differentiation in Neural Crest Cells and Development of the Cardiac Outflow Tract

Cited by 63 publications

References 44 publications

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

The formation and function of the cardiac conduction system

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