A HAND2 Cistrome Controls Heart Development and the Endothelial-Mesenchymal Transition during Cardiac Valve Formation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE73368 | GEO | 2017/05/24
SECONDARY ACCESSION(S): PRJNA296808
REPOSITORIES: GEO
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Project description:The HAND2 transcriptional regulator controls cardiac development and we uncover addition essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted and we combined ChIP-Seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.
2017-05-10 | GSE94246 | GEO
Project description:The basic-helix-loop-helix transcription factor HAND2 plays a critical role in endocardium to myocardium signaling during cardiac morphogenesis through its role within the NOTCH signaling pathway. Hand2 endocardial deletion (H2CKOs) results in embryonic lethality by E13.5 due to tricuspid atresia (TA) or double inlet left ventricle (DILV) with accompanying intraventricular septum defects, multiple septa, and hypo-trabeculated ventricles. In addition, H2CKOs also exhibit an increased density of coronary lumens. In order to understand the underlying regulatory mechanisms that cause these phenotypes, we undertook a single cell transcriptome analysis of E11.5 H2CKOs hearts.
2023-01-09 | GSE210221 | GEO
Project description:Our previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity. To identify the downstream targets of Hand2 in the uterus, we performed gene expression profling of uterine stromal cells isolated from Hand2-null mice and the corresponding controls on day4 of pregnancy (the time of implantation). The microarray results revealed elevated expression of mRNAs corresponding to several members of the fibroblast growth factor family in uterine stroma of Hand2-ablated mice. These factors act as paracrine mediators of mitogenic effects of estrogen on the epithleium. Thus, Hand2 is a critical regulator of the uteirne stromal-epithelial communication that directs proper steroid regulation conducive for establshment of pregnancy. We performed conditional ablation of Hand2 in the mouse uterus using the PRcre mouse model. As Hand2 expression is restricted to stromal comaprtment, we isolated uterine stromal cells from day4 pregnant mice (n=5 for each genotype), purified total RNA from these cells, pooled these samples and then hybridized to high density affymetrix microarrays. Control vs. KO.
2011-06-03 | E-GEOD-25881 | biostudies-arrayexpress
Project description:Acquisition of the lower jaw (mandible) was evolutionarily important for jawed vertebrates. In humans, syndromic craniofacial malformations often accompany jaw anomalies. Hand2 is involved in coordinating the developmental network of mandibles and the oral apparatus through Hand2-downstream genes and is therefore a major determinant of jaw identity. We used microarrays to detail the global programme of gene expression involved in mandible specification and identified distinct classes of up-regulated genes during this process. Wild-type and Hand2 mutant (Hand2 CAT/+; Wnt1-Cre) embryos were collected at Embryonic day (E) 11.5 or E12.5 for RNA extraction and hybridization on Affymetrix microarrays.
2015-12-15 | E-GEOD-75805 | biostudies-arrayexpress
Project description:In humans, cardiac hypertrophy is the principal risk factor for the development of overt heart failure and sudden cardiac death from lethal arrhythmias. Although aberrant reactivation of fetal² gene programs is intricately linked to maladaptive hypertrophy of postnatal cardiomyocytes, loss of cardiac function and heart failure, the transcription factors driving these gene programs remain ill defined. We report that the basic helix-loop-helix (bHLH) transcription factor dHAND/Hand2 is re-expressed in the mammalian postnatal myocardium in response to stress signaling. Interestingly, mutant mice overexpressing Hand2 in otherwise healthy ventricular myocytes developed a phenotype of pathological hypertrophy. In contrast, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. These data suggest a critical role for the Hand2 transcription factor during hypertrophic remodeling and heart failure. To gain more mechanistically insight in the processes underlying heart failure, we here identified Hand2 target genes by microarray gene expression profiling. RNA samples were collected 4 weeks after sham or TAC surgery (to induce pressure overload) of both tamoxifen-treated Hand2f/f (WT) and MCM-Hand2f/f (KO) mice.
2013-11-15 | E-MTAB-1821 | biostudies-arrayexpress
Project description:Heart formation requires the fusion of bilateral cardiomyocyte populations as they move toward the embryonic midline. The bHLH transcription factor Hand2 is essential for cardiac fusion; however, the effector genes that execute this function of Hand2 are unknown. Here, we provide the first evidence for a downstream component of the Hand2 pathway that mediates cardiac morphogenesis. Although hand2 is expressed in cardiomyocytes, mosaic analysis demonstrates that hand2 plays a non-autonomous role in regulating cardiomyocyte movement. Gene expression profiles reveal heightened expression of fibronectin 1 (fn1) in hand2 mutant embryos. Reciprocally, overexpression of hand2 leads to decreased Fibronectin levels. Furthermore, reduction of fn1 function enables rescue of cardiac fusion in hand2 mutants: bilateral cardiomyocyte populations merge and exhibit improved tissue architecture, albeit without major changes in apicobasal polarity. Together, our data provide a novel example of a tissue creating a favorable environment for its morphogenesis: the Hand2 pathway establishes an appropriate environment for cardiac fusion through negative modulation of Fn1 levels. Embryos from three independent hand2 mutant (hanS6 allele) heterozyogous crosses were collected. Examination of Tg(myl7:egfp) expression allow sorting of hand2 mutant embryos from their wild-type siblings.
2010-08-03 | E-GEOD-23381 | biostudies-arrayexpress
Project description:The knockdown of HAND2 affects the regional chromation modification.
2023-03-29 | GSE184058 | GEO
Project description:The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.
2022-01-14 | E-MTAB-9727 | biostudies-arrayexpress
Project description:HAND2 assists MYCN bind to DNA.
2023-03-29 | GSE184059 | GEO
Project description:hand2 reporter-expressing cardiac cells fail to migrate to the midline. To investigate the underlying molecular changes, we sequenced mRNA from 3900 and 3836 hand2 reporter-expressing single cells from 24 hpf hand2 FLD-/- and hand2 FLD+/? sibling embryos, respectively. Furthermore, hand2 is broadly expressed within the LPM, which gives rise to various cell lineages and tissues including the cardiovascular system, blood, kidneys, mesothelium, and limb connective tissue. To further investigate the requirement of Hand2 in the early events of cardiac lineage specification in zebrafish, we aim to characterize the early hand2 expressing cardiac precursors by using embryonic CM H3K27ac ChIP-seq and ATAC-seq data.
2024-08-01 | GSE241971 | GEO