scholarly journals Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

2017 ◽  
Author(s):  
Xin Sun ◽  
Swetansu K. Hota ◽  
Yu-Qing Zhou ◽  
Stefanie Novak ◽  
Dario Miguel-Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Gene Networks ◽  
Contractile Function ◽  
Conditional Deletion ◽  
Genes Encoding ◽  
Organ Specific ◽  
Chromatin Remodeling Complexes ◽  
And Function

AbstractHow gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

scholarly journals Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-48-SCI-48
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Developmental Disorders ◽  
Human Cancer ◽  
Malignant Rhabdoid Tumor ◽  
Advisory Committees ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Therapeutic Development ◽  
Chromatin Remodeling Complexes ◽  
And Function

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression

2001 ◽  
Vol 21 (5) ◽  
pp. 1730-1736 ◽  
Author(s):  
Benoit G. Bruneau ◽  
Zheng-Zheng Bao ◽  
Diane Fatkin ◽  
Jose Xavier-Neto ◽  
Dimitrios Georgakopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Contractile Function ◽  
Specific Gene ◽  
Postnatal Life ◽  
Helix Loop Helix ◽  
And Function ◽  
Expression Program ◽  
Deficient Mice

ABSTRACT To define the role of Irx4, a member of the Iroquoisfamily of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designatedIrx4 Δex2/Δex2) was normal during embryogenesis and in early postnatal life. AdultIrx4 Δex2/Δex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy,Irx4 Δex2/Δex2 hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increasedIrx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and α-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and β-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

scholarly journals ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression

2020 ◽  
Vol 6 (29) ◽  
pp. eaaz3440 ◽  
Author(s):  
Hui Shi ◽  
Ting Tao ◽  
Brian J. Abraham ◽  
Adam D. Durbin ◽  
Mark W. Zimmerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Neuroblastoma Cells ◽  
Tumor Development ◽  
Mesenchymal Cell ◽  
Drug Resistant ◽  
Zebrafish Model ◽  
Mesenchymal Transition ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes

Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.

scholarly journals Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

Biology Open ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. bio029512 ◽  
Author(s):  
Xin Sun ◽  
Swetansu K. Hota ◽  
Yu-Qing Zhou ◽  
Stefanie Novak ◽  
Dario Miguel-Perez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Chromatin Remodeling Complex ◽  
And Function

scholarly journals The GAGA factor is required in the early Drosophila embryo not only for transcriptional regulation but also for nuclear division

Development ◽  
1996 ◽  
Vol 122 (4) ◽  
pp. 1113-1124 ◽  
Author(s):  
K.M. Bhat ◽  
G. Farkas ◽  
F. Karch ◽  
H. Gyurkovics ◽  
J. Gausz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
In Vitro Transcription ◽  
Drosophila Embryo ◽  
Gaga Factor ◽  
Early Drosophila Embryo ◽  
Hypersensitive Sites ◽  
And Function ◽  
Stimulatory Factor

The GAGA protein of Drosophila was first identified as a stimulatory factor in in vitro transcription assays using the engrailed and Ultrabithorax promoters. Subsequent studies have suggested that the GAGA factor promotes transcription by blocking the repressive effects of histones; moreover, it has been shown to function in chromatin remodeling, acting together with other factors in the formation of nuclease hypersensitive sites in vitro. The GAGA factor is encoded by the Trithorax-like locus and in the studies reported here we have used the maternal effect allele Trl13C to examine the functions of the protein during embryogenesis. We find that GAGA is required for the proper expression of a variety of developmental loci that contain GAGA binding sites in their upstream regulatory regions. The observed disruptions in gene expression are consistent with those expected for a factor involved in chromatin remodeling. In addition to facilitating gene expression, the GAGA factor appears to have a more global role in chromosome structure and function. This is suggested by the spectrum of nuclear cleavage cycle defects observed in Trl13C embryos. These defects include asynchrony in the cleavage cycles, failure in chromosome condensation, abnormal chromosome segregation and chromosome fragmentation. These defects are likely to be related to the association of the GAGA protein with heterochromatic satellite sequences which is observed throughout the cell cycle.

scholarly journals Comparative Analysis of SWIRM Domain-Containing Proteins in Plants

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yan Gao ◽  
Songguang Yang ◽  
Lianyu Yuan ◽  
Yuhai Cui ◽  
Keqiang Wu
Keyword(s):  
Chromatin Remodeling ◽  
Essential Role ◽  
Atp Hydrolysis ◽  
Chromatin Modification ◽  
Dna Binding Proteins ◽  
Plant Responses ◽  
Chromosomal Proteins ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes ◽  
Affect Gene Expression

Chromatin-remodeling complexes affect gene expression by using the energy of ATP hydrolysis to locally disrupt or alter the association of histones with DNA. SWIRM (Swi3p, Rsc8p, and Moira) domain is an alpha-helical domain of about 85 residues in chromosomal proteins. SWIRM domain-containing proteins make up large multisubunit complexes by interacting with other chromatin modification factors and may have an important function in plants. However, little is known about SWIRM domain-containing proteins in plants. In this study, 67 SWIRM domain-containing proteins from 6 plant species were identified and analyzed. Plant SWIRM domain proteins can be divided into three distinct types: Swi-type, LSD1-type, and Ada2-type. Generally, the SWIRM domain forms a helix-turn-helix motif commonly found in DNA-binding proteins. The genes encoding SWIRM domain proteins inOryza sativaare widely expressed, especially in pistils. In addition,OsCHB701andOsHDMA701were downregulated by cold stress, whereasOsHDMA701andOsHDMA702were significantly induced by heat stress. These observations indicate that SWIRM domain proteins may play an essential role in plant development and plant responses to environmental stress.

scholarly journals Dioxin Disrupts Dynamic DNA Methylation Patterns in Genes That Govern Cardiomyocyte Maturation

2020 ◽  
Vol 178 (2) ◽  
pp. 325-337
Author(s):  
Matthew de Gannes ◽  
Chia-I Ko ◽  
Xiang Zhang ◽  
Jacek Biesiada ◽  
Liang Niu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Heart Development ◽  
Expression Patterns ◽  
Embryonic Stem Cell Line ◽  
Molecular Networks ◽  
Unknown Etiology ◽  
Postnatal Maturation ◽  
Complex Interactions ◽  
And Function

Abstract Congenital heart disease (CHD), the leading birth defect worldwide, has a largely unknown etiology, likely to result from complex interactions between genetic and environmental factors during heart development, at a time when the heart adapts to diverse physiological and pathophysiological conditions. Crucial among these is the regulation of cardiomyocyte development and postnatal maturation, governed by dynamic changes in DNA methylation. Previous work from our laboratory has shown that exposure to the environmental toxicant tetrachlorodibenzo-p-dioxin (TCDD) disrupts several molecular networks responsible for heart development and function. To test the hypothesis that the disruption caused by TCDD in the heart results from changes in DNA methylation and gene expression patterns of cardiomyocytes, we established a stable mouse embryonic stem cell line expressing a puromycin resistance selectable marker under control of the cardiomyocyte-specific Nkx2-5 promoter. Differentiation of these cells in the presence of puromycin induces the expression of a large suite of cardiomyocyte-specific markers. To assess the consequences of TCDD treatment on gene expression and DNA methylation in these cardiomyocytes, we subjected them to transcriptome and methylome analyses in the presence of TCDD. Unlike control cardiomyocytes maintained in vehicle, the TCDD-treated cardiomyocytes showed extensive gene expression changes, with a significant correlation between differential RNA expression and DNA methylation in 111 genes, many of which are key elements of pathways that regulate cardiovascular development and function. Our findings provide an important clue toward the elucidation of the complex interactions between genetic and epigenetic mechanisms after developmental TCDD exposure that may contribute to CHD.

Functional diversity of ISWI complexes

2004 ◽  
Vol 82 (4) ◽  
pp. 482-489 ◽  
Author(s):  
Sara S Dirscherl ◽  
Jocelyn E Krebs
Keyword(s):  
Chromatin Remodeling ◽  
Catalytic Core ◽  
Chromatin Remodelers ◽  
Form And Function ◽  
Curr Opin Cell Biol ◽  
Chromatid Cohesion ◽  
Chromatin Remodeling Complexes ◽  
And Function ◽  
Diverse Groups ◽  
Nuclear Processes

The yeast SWI/SNF ATP-dependent chromatin remodeling complex was first identified and characterized over 10 years ago (F. Winston and M. Carlson. 1992. Trends Genet. 8: 387–391.) Since then, the number of distinct ATP-dependent chromatin remodeling complexes and the variety of roles they play in nuclear processes have become dizzying (J.A. Martens and F. Winston. 2003. Curr. Opin. Genet. Dev. 13: 136–142; A. Vacquero et al. 2003. Sci. Aging Knowledge Environ. 2003: RE4) — and that does not even include the companion suite of histone modifying enzymes, which exhibit a comparable diversity in both number of complexes and variety of functions (M.J. Carrozza et al. 2003. Trends Genet. 19: 321–329; W. Fischle et al. 2003. Curr. Opin. Cell Biol. 15: 172–183; M. Iizuka and M.M. Smith. 2003. Curr. Opin. Genet. Dev. 13: 1529–1539). This vast complexity is hardly surprising, given that all nuclear processes that involve DNA — transcription, replication, repair, recombination, sister chromatid cohesion, etc. — must all occur in the context of chromatin. The SWI/SNF-related ATP-dependent remodelers are divided into a number of subfamilies, all related by the SWI2/SNF2 ATPase at their catalytic core. In nearly every species where researchers have looked for them, one or more members of each subfamily have been identified. Even the budding yeast, with its comparatively small genome, contains eight different chromatin remodelers in five different subfamilies. This review will focus on just one subfamily, the Imitation Switch (ISWI) family, which is proving to be one of the most diverse groups of chromatin remodelers in both form and function.

scholarly journals The Drosophila SWI/SNF chromatin-remodeling complexes BAP and PBAP play separate roles in regulating growth and cell fate during regeneration

2018 ◽  
Author(s):  
Yuan Tian ◽  
Rachel K. Smith-Bolton
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Tissue Regeneration ◽  
Wing Disc ◽  
Epithelial Tissue ◽  
Growth Promoter ◽  
Jnk Signaling ◽  
Regenerative Growth ◽  
Chromatin Remodeling Complexes

AbstractTo regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation in Drosophila imaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoter Myc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing expression of the posterior gene engrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate.Summary statementDuring regeneration of the Drosophila wing disc, the SWI/SNF PBAP complex is required for regenerative growth and expression of JNK signaling targets, while the BAP complex maintains posterior cell fate.

scholarly journals The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4720-4732 ◽  
Author(s):  
Veneta Krasteva ◽  
Manuel Buscarlet ◽  
Abigail Diaz-Tellez ◽  
Marie-Anne Bernard ◽  
Gerald R. Crabtree ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chromatin Remodeling ◽  
Progenitor Cell ◽  
Cell Function ◽  
Adult Stem Cell ◽  
Hemopoietic Stem Cell ◽  
Conditional Deletion ◽  
Chromatin Remodeling Complexes ◽  
A Subunit

Abstract ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes are emerging as key regulators of embryonic and adult stem cell function. Particularly intriguing are the findings that specialized assemblies of BAF complexes are required for establishing and maintaining pluripotent and multipotent states in cells. However, little is known on the importance of these complexes in normal and leukemic hemopoiesis. Here we provide the first evidence that the actin-related protein BAF53a, a subunit of BAF complexes preferentially expressed in long-term repopulating stem cells, is essential for adult hemopoiesis. Conditional deletion of BAF53a resulted in multilineage BM failure, aplastic anemia, and rapid lethality. These severe hemopoietic defects originate from a proliferative impairment of BM HSCs and progenitors and decreased progenitor survival. Using hemopoietic chimeras, we show that the impaired function of BAF53a-deficient HSCs is cell-autonomous and independent of the BM microenvironment. Altogether, our studies highlight an unsuspected role for BAF chromatin remodeling complexes in the maintenance of HSC and progenitor cell properties.

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