SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer.

Despite progress significant advances in immunotherapy for some solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive poorly responsive to such interventions, largely due to its highly immunosuppressive tumor microenvironment (TME) with limited CD8+ T cell infiltration. This study explores the role of the epigenetic factor Sin3B in the PDAC TME. Using murine PDAC models, we found that tumor cell-intrinsic Sin3B loss reshapes the TME, increasing CD8+ T cell infiltration and cytotoxicity, thus impeding tumor progression and enhancing sensitivity to anti-PD1 treatment. Sin3B-deficient tumor cells exhibited amplified CXCL9/10 secretion in response to Interferon-gamma (IFNγ), creating a positive feedback loop via the CXCL9/10-CXCR3 axis, thereby intensifying the anti-tumor immune response against PDAC. Mechanistically, extensive epigenetic regulation is uncovered by Sin3B loss, particularly enhanced H3K27Ac distribution on genes related to immune responses in PDAC cells. Consistent with the murine model findings, analysis of human PDAC samples revealed a significant inverse correlation between SIN3B levels and both CD8+ T cell infiltration and CXCL9/10 expression. Notebly, PDAC patients with lower SIN3B expression showed a more favorable response to anti-PD1 therapy. The findings suggest that targeting SIN3B can enhance cytotoxic T cell infiltration into the tumor site and improve immunotherapy efficacy in PDAC, offering potential avenues for therapeutic biomarker or target in this challenging disease.

miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.

Senescence is a cell fate driven by different types of stress that results in exit from the cell cycle and expression of an inflammatory senescence-associated secretory phenotype (SASP). Here, we demonstrate that stable overexpression of miR-96-5p was sufficient to induce cellular senescence in the absence of genotoxic stress, inducing expression of certain markers of early senescence including SASP factors while repressing markers of deep senescence including LINE-1 and type 1 interferons. Stable miR-96-5p overexpression led to genome-wide changes in heterochromatin followed by epigenetic activation of p16Ink4a, p21Cip1, and SASP expression, induction of a marker of DNA damage, and induction of a transcriptional signature similar to other senescent lung and endothelial cell types. Expression of miR-96-5p significantly increased following senescence induction in culture cells and with aging in tissues from naturally aged and Ercc1-/Δ progeroid mice. Mechanistically, miR-96-5p directly suppressed expression of SIN3B and SIN3 corepressor complex constituents KDM5A and MORF4L2, and siRNA-mediated knockdown of these transcriptional regulators recapitulated the senescent phenotype. In addition, pharmacologic inhibition of the SIN3 complex suppressed senescence and SASP markers. These results clearly demonstrate that a single microRNA is sufficient to drive early senescence in the absence of genotoxic stress through targeting epigenetic and transcriptional regulators, identifying novel targets for the development of senotherapeutics.

T-regulatory cells require Sin3a for stable expression of Foxp3.

Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated. Developmental deletion of Sin3a from Foxp3+ Tregs resulted in the rapid onset of fatal autoimmunity. Treg numbers were greatly reduced, while residual Tregs had impaired suppressive function. Mice also showed effector T-cell activation, autoantibody production, and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of Foxp3 with a complete lack of CNS2 CpG demethylation. In addition, Foxp3 protein stability was impaired with an increased ex-Treg population. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.

Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth.

Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

Histone deacetylase complexes: Structure, regulation and function.

Histone deacetylases (HDACs) are key epigenetic regulators, and transcriptional complexes with deacetylase function are among the epigenetic corepressor complexes in the nucleus that target the epigenome. HDAC-bearing corepressor complexes such as the Sin3 complex, NuRD complex, CoREST complex, and SMRT/NCoR complex are common in biological systems. These complexes activate the otherwise inactive HDACs in a solitary state. HDAC complexes play vital roles in the regulation of key biological processes such as transcription, replication, and DNA repair. Moreover, deregulated HDAC complex function is implicated in human diseases including cancer. Therapeutic strategies targeting HDAC complexes are being sought actively. Thus, illustration of the nature and composition of HDAC complexes is vital to understanding the molecular basis of their functions under physiologic and pathologic conditions, and for designing targeted therapies. This review presents key aspects of large multiprotein HDAC-bearing complexes including their structure, function, regulatory mechanisms, implication in disease development, and role in therapeutics.

Silencing of the long non-coding RNA LINC00265 triggers autophagy and apoptosis in lung cancer by reducing protein stability of SIN3A oncogene.

Background: Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes. Their dysregulation has been closely associated with tumorigenesis. LINC00265 is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer. However, the mechanism underlying its function in cancer progression remains poorly understood. Methods: Here, the regulatory role of LINC00265 in lung adenocarcinoma was examined using lung cancer cell lines, clinical samples, and xenografts. Results: We found that high levels of LINC00265 expression were associated with shorter overall survival rate of patients, whereas knockdown of LINC00265 inhibited proliferation of cancer cell lines and tumor growth in xenografts. Western blot and flow cytometry analyses indicated that silencing of LINC00265 induced autophagy and apoptosis. Moreover, we showed that LINC00265 interacted with and stabilized the transcriptional co-repressor Switch-independent 3a (SIN3A), which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner. Silencing of SIN3A also reduced proliferation of lung cancer cells, which was correlated with the induction of autophagy. These observations raise the possibility that LINC00265 functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma. Conclusions: Our findings thus identify SIN3A as a LINC00265-associated protein and should help to understand the mechanism underlying LINC00265-mediated oncogenesis.

Correlation between FOXN3-SIN3A complex expression in peripheral blood and non-syndromic cleft lip and palate in Xinjiang.

OBJECTIVES: This work aimed to study the correlation between FOXN3-SIN3A complex expression and non-syndromic oral clefts (NSOC) in Xinjiang. METHODS: In this study, 60 patients with NSOC attending the People's Hospital of Xinjiang Uygur Autonomous Region were recruited into the case group, including 30 cleft lip with or without cleft palate (NSCL/P), 30 cleft palate only (CPO), and 30 healthy children in the control group. The expression levels of FOXN3, SIN3A, and NEAT1 in peripheral blood of each group were detected by high-throughput second-generation sequencing technology and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to analyze the diagnostic efficiency of NSOC. RESULTS: The comparison of the NSOC and control groups showed that FOXN3, SIN3A, and NEAT1 genes increased compared with the control group. The differences were all statistically significant (P<0.05). The AUCs of FOXN3, SIN3A, and NEAT1 in the NSCL/P group were 0.933 [95%CI=(0.864, 1.000)], 0.822 [(95%CI=(0.713, 0.932)], and 1.000[95%CI= (1.000, 1.000)], respectively. The AUCs of FOX-N3, SIN3A, and NEAT1 in the CPO group were 0.891 [95%CI=(0.806, 0.976)], 0.688 [95%CI=(0.552, 0.824)], and 1.000 [95%CI=(1.000, 1.000)], respectively. CONCLUSIONS: The results showed a correlation between the rising gene expression of FOXN3, SIN3A, and NEAT1 in peripheral blood and the occurrence of NSOC in Xinjiang. This work provides a theoretical basis for further study of the FOXN3-SIN3A complex as biomarkers to facilitate the early screening, disease prediction, and early prevention of NSOC.

A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene.

Introduction: The Witteveen-Kolk syndrome (WITKOS) (OMIM: 613406) is a heterogeneous emerging disorder caused by pathogenic variants or microdeletions encompassing the SIN3A gene (SIN3 Transcription Regulator Family Member A). It is characterized by distinctive facial features, developmental delay, intellectual disability, microcephaly, short stature, and subtle anomalies on brain magnetic resonance imaging (MRI). To date, about 50 patients have been reported in the medical literature. Patient Presentation: In this article, we reported a patient with classic findings of WITKOS including global developmental delay, microcephaly, hypotonia, vomiting, malnutrition, autistic and dysmorphic facial features, and cardiac abnormalities. Also, a barium esophagogram suggested severe motility disorder and gastroesophageal reflux disease. Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2, including the whole SIN3A gene. We have also summarized the clinical features of WITKOS patients in the medical literature and cardiac abnormalities detected in 4 out of 10 patients in studies that clearly state that cardiac examination was performed in the patients. Conclusion: Our findings showed that cardiac defects are not uncommon findings in WITKOS. Physicians should also be aware of reflux disease and motility disorder in patients with feeding difficulty together with early cardiac examination in terms of an improved quality of life in WITKOS patients.

Understanding Longevity: SIN-3 and DAF-16 Revealed as Independent Players in Lifespan Regulation.

Aging is the process of gradual physio-biochemical deterioration. Although aging is inevitable, healthy aging is the key to individual and communal well-being. Therefore, it is essential to understand the regulation of aging. SIN-3/Sin-3 is a unique regulatory protein that regulates aging without DNA-binding activity. It functions by establishing multiple protein interactions. To understand the functional mechanism of this transcriptional regulator, the Caenorhabditis elegans protein interactome was assessed for SIN-3 interactions. DAF-16/FOXO emerged as one of the leading contenders for SIN-3-mediated regulation of aging. This study looks at the concerted role of SIN-3 and DAF-16 proteins in lifespan regulation. Phenotypic profiling for the mutants of these genes shows the functional accord between these 2 proteins with similar functions in stress response and vital biological processes. However, there were no significant physical interactions when checked for protein-protein interaction between SIN-3 and DAF-16 proteins. C. elegans genomics and transcriptomics data also indicated the possibilities of concerted gene regulation. This genetic regulation is more likely related to SIN-3 dominance on DAF-16 function. Overall, SIN-3 and DAF-16 proteins have strong functional interactions that ensure healthy aging. The influence of SIN-3 on DAF-16-mediated stress response is one of their convergence points in longevity regulation.

Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape.

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.

Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome.

Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing SIN3A. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of SIN3A or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in SIN3A, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to SIN3A in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.

Distinct regions within SAP25 recruit O-linked glycosylation, DNA demethylation, and ubiquitin ligase and hydrolase activities to the Sin3/HDAC complex.

Epigenetic control of gene expression is crucial for maintaining gene regulation. Sin3 is an evolutionarily conserved repressor protein complex mainly associated with histone deacetylase (HDAC) activity. A large number of proteins are part of Sin3/HDAC complexes, and the function of most of these members remains poorly understood. SAP25, a previously identified Sin3A associated protein of 25 kDa, has been proposed to participate in regulating gene expression programs involved in the immune response but the exact mechanism of this regulation is unclear. SAP25 is not expressed in HEK293 cells, which hence serve as a natural knockout system to decipher the molecular functions uniquely carried out by this Sin3/HDAC subunit. Using molecular, proteomic, protein engineering, and interaction network approaches, we show that SAP25 interacts with distinct enzymatic and regulatory protein complexes in addition to Sin3/HDAC. While the O-GlcNAc transferase (OGT) and the TET1 /TET2/TET3 methylcytosine dioxygenases have been previously linked to Sin3/HDAC, in HEK293 cells, these interactions were only observed in the affinity purification in which an exogenously expressed SAP25 was the bait. Additional proteins uniquely recovered from the Halo-SAP25 pull-downs included the SCF E3 ubiquitin ligase complex SKP1/FBXO3/CUL1 and the ubiquitin carboxyl-terminal hydrolase 11 (USP11), which have not been previously associated with Sin3/HDAC. Finally, we use mutational analysis to demonstrate that distinct regions of SAP25 participate in its interaction with USP11, OGT/TETs, and SCF(FBXO3).) These results suggest that SAP25 may function as an adaptor protein to coordinate the assembly of different enzymatic complexes to control Sin3/HDAC-mediated gene expression.

SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability.

During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.

Suppression of the long non-coding RNA LINC01279 triggers autophagy and apoptosis in lung cancer by regulating FAK and SIN3A.

Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear. Here, we analyzed the function of LINC01279 in lung adenocarcinoma using clinical samples, xenografts, and non-small-cell lung cancer cell lines. We found that LINC01279 is highly expressed in lung adenocarcinoma and may be considered as a predictive factor for this cancer. Knockdown of LINC01279 prevents tumor growth in xenografts and in cancer cell lines by activating autophagy and apoptosis. Molecularly, we revealed that LINC01279 regulates the expression of focal adhesion kinase and extracellular-regulated kinase signaling. In addition, it complexes with and stabilizes the transcriptional co-repressor SIN3A protein. Suppression of focal adhesion kinase and SIN3A also induces apoptosis and prevents tumor progression, suggesting that they may at least in part mediate the oncogenic activity of LINC01279. These results identify LINC01279 as a possible oncogene that plays an important role in the development of lung cancer. Our findings provide insights into the mechanism underlying LINC01279-mediated oncogenesis of lung adenocarcinoma. They may help to discover potential therapeutic targets for cancer diagnosis and prognosis.

Analysis of Bulk Transcriptome Sequencing Data and in vitro Experiments Reveal SIN3A as a Potential Target for Diabetic Foot Ulcer.

Background: Diabetic foot ulcers (DFUs) represent a severe complication of diabetes associated with reduced quality of life, lower limb amputations, hospitalizations, increased incidence, and mortality. Importantly, a significant number of pathogenic genes remain unexplored in DFUs. Methods: A series of bioinformatics analyses were performed on publicly available bulk transcriptome sequencing datasets GSE134431 and GSE80178 to explore the transcriptomic changes in DFUs and select core genes for in vitro functional validation. In a focused examination, the differential expression analysis unveiled distinctions in gene expression patterns between DFUs and non-ulcerated diabetic skin tissues. Enriched functional annotations of differentially expressed genes were explored using the DAVID online tool. Protein-protein interaction analysis was conducted to investigate interactions among differentially expressed genes and select core genes. Knockdown or overexpression of core genes in HaCaT keratinocytes was performed to assess their impact on cell proliferation and migration. Results: Ten core genes were identified. Cell Counting Kit-8 (CCK-8) and scratch assays demonstrated that downregulation of the core gene SIN3A significantly inhibited the migration and proliferation of HaCaT keratinocytes, while overexpression of SIN3A reversed the high-glucose-induced suppression of HaCaT cell viability and migration. Conclusion: SIN3A expression is downregulated in DFUs. In vitro, SIN3A promotes the proliferation and migration of HaCaT keratinocytes, suggesting it may be a potential therapeutic target for DFUs.

HDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes.

Histone deacetylases (HDACs) are pivotal in transcriptional regulation, and their dysregulation has been associated with various diseases including cancer. One of the critical roles of HDAC-containing complexes is the deacetylation of histone tails, which is canonically linked to transcriptional repression. Previous research has indicated that HDACs are recruited to cell-cycle gene promoters through the RB protein or the DREAM complex via SIN3B and that HDAC activity is essential for repressing G1/S and G2/M cell-cycle genes during cell-cycle arrest and exit. In this study, we sought to explore the interdependence of DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. We found that genetic knockout of SIN3B did not lead to derepression of cell-cycle genes in non-proliferating HCT116 and C2C12 cells. A combined loss of SIN3A and SIN3B resulted in a moderate upregulation in mRNA expression of several cell-cycle genes in arrested HCT116 cells, however, these effects appeared to be independent of DREAM or RB. Furthermore, HDAC inhibition did not induce a general upregulation of RB and DREAM target gene expression in arrested transformed or non-transformed cells. Our findings provide evidence that E2F:RB and DREAM complexes can repress cell-cycle genes without reliance on HDAC activity.

Analysis of the chromatin landscape and RNA polymerase II binding at SIN3-regulated genes.

The chromatin environment has a significant impact on gene expression. Chromatin structure is highly regulated by histone modifications and RNA polymerase II binding dynamics. The SIN3 histone modifying complex regulates the chromatin environment leading to changes in gene expression. In Drosophila melanogaster, the Sin3A gene is alternatively spliced to produce different protein isoforms, two of which include SIN3 220 and SIN3 187. Both SIN3 isoforms are scaffolding proteins that interact with several other factors to regulate the chromatin landscape. The mechanism through which the SIN3 isoforms regulate chromatin is not well understood. Here, we analyze publicly available data sets to allow us to ask specific questions on how SIN3 isoforms regulate chromatin and gene activity. We determined that genes repressed by the SIN3 isoforms exhibited enrichment in histone H3K4me2, H3K4me3, H3K14ac and H3K27ac near the transcription start site. We observed an increase in the amount of paused RNA polymerase II on the promoter of genes repressed by the isoforms as compared to genes that require SIN3 for maximum activation. Furthermore, we analyzed a subset of genes regulated by SIN3 187 that suggest a mechanism in which SIN3 187 might exhibit hard regulation as well as soft regulation. Data presented here expand our knowledge of how the SIN3 isoforms regulate the chromatin environment and RNA polymerase II binding dynamics.

SIN-3 acts in distinct complexes to regulate the germline transcriptional program in Caenorhabditis elegans.

The transcriptional co-regulator SIN3 influences gene expression through multiple interactions that include histone deacetylases. Haploinsufficiency and mutations in SIN3 are the underlying cause of Witteveen-Kolk syndrome and related intellectual disability and autism syndromes, emphasizing its key role in development. However, little is known about the diversity of its interactions and functions in developmental processes. Here, we show that loss of SIN-3, the single SIN3 homolog in Caenorhabditis elegans, results in maternal-effect sterility associated with de-regulation of the germline transcriptome, including de-silencing of X-linked genes. We identify at least two distinct SIN3 complexes containing specific histone deacetylases and show that they differentially contribute to fertility. Single-cell, single-molecule fluorescence in situ hybridization reveals that in sin-3 mutants the X chromosome becomes re-expressed prematurely and in a stochastic manner in individual germ cells, suggesting a role for SIN-3 in its silencing. Furthermore, we identify histone residues whose acetylation increases in the absence of SIN-3. Together, this work provides a powerful framework for the in vivo study of SIN3 and associated proteins.

Sin3a associated protein 130 kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130 kDa (Sap130), part of the chromatin modifying SIN3A/HDAC complex, as a gene contributing to the etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cardiac function were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.