Sarcomeric regulation of serum response factor signaling in cardiomyocyte maturation by actinin-2
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ABSTRACT:
PROVIDER: PRJNA561289 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10006733.fastq.gz | Fastqsanger.gz | |||
| SRR10006734.fastq.gz | Fastqsanger.gz | |||
| SRR10006735.fastq.gz | Fastqsanger.gz | |||
| SRR10006736.fastq.gz | Fastqsanger.gz | |||
| SRR10006737.fastq.gz | Fastqsanger.gz |
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Project description:This study establishes the homeodomain only protein, HOPX, as a determinant controlling the molecular switch between cardiomyocyte progenitor and maturation gene programs. This dataset is about time-course CAGE (capped analysis of gene expression) data with genome-wide active transcription footprinting. HOPX CRISPRi cells were differentiated into cardiomyocytes ± DOX and analyzed by CAGE sequencing, among other methods. The study revealed that HOPX interacts with and controls core cardiac networks by regulating the activity of mutually exclusive developmental gene programs.
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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
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Project description:We identify the global transcriptional changes that occur between homeostatic and proliferative cardiomyocytes in the zebrafish heart and uncover an essential role for H3K27me3 deposition in facilitating successful myocardial regeneration. Specifically, we learned that cardiomyocyte proliferation is accompanied by downregulation of sarcomeric and cytoskeletal components and upregulation of the polycomb methylase Ezh2. Using ChIPseq, we demonstrate that this transcriptional repression is associated with deposition of new H3K27me3 modifications over the promoters. Using new genetic zebrafish lines that allow for inducible and cardiomyocyte-specific expression of a mutant form of histone 3 that is unable to be tri-methylated on lysine 27 (H3.3K27M), we discovered that addition of H3K27me3 marks is essential for cardiac regeneration in vivo. Earlier in the regenerative window, we found that H3.3K27M–expressing wound edge cardiomyocytes aberrantly maintain homeostatic levels of sarcomeric and actomyosin gene expression and show significant retention of sarcomere structure. While DNA replication occurs normally in these H3.3K27M cardiomyocytes, we observed significant increases in cardiomyocyte nucleation, a phenotype indicative of cytokinesis failures. In addition, nuclear density at the wound edge increases as new cardiomyocytes fail to colonize the injured area. Together, our study reveals that production of new cardiomyocytes and their infiltration into the injured region relies on H3K27me3-mediated sarcomeric and actomyosin cytoskeletal gene repression.
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Project description:Background: There is a limited capacity to repair damage in the mammalian heart after birth, which is primarily due to the inability of cardiomyocytes to proliferate after birth. This is in contrast to zebrafish and salamander, in which cardiomyocytes retain the ability to proliferate throughout life and can regenerate their heart after significant damage. Recent studies in zebrafish and rodents implicate microRNAs (miRNAs) in the regulation of genes responsible for cardiac cell cycle progression and regeneration, in particular, miR-133a, the miR-15 family, miR-199a and miR-590. However, the significance of these miRNAs and miRNA in general in the regulation of cardiomyocyte proliferation in large mammals, including humans, where the timing of heart development relative to birth is very different than in rodents, is unclear. To determine the involvement of miRNAs in the down-regulation of cardiomyocyte proliferation occurring before birth in large mammals, we investigated miRNA and target gene expression in sheep hearts before and after birth. The experimental approach included targeted transcriptional profiling of miRNA and target mRNA previously identified in rodent studies as well as genome-wide miRNA profiling using microarrays. Results: The cardiac expression of miR-133a increased and its target gene IGF1R decreased with increasing age, reaching their respective maximum and minimum abundance when the majority of ovine cardiomyocytes were quiescent. The expression of the miR-15 family members was variable with age, however, four of their target genes decreased with age. These latter profiles are inconsistent with the direct involvement of this family of miRNA in cardiomyocyte quiescence in late gestation sheep. The expression patterns of ‘pro-proliferative’ miR-199a and miR-590 were also inconsistent with their involvement in cardiomyocyte quiescence. Consequently, miRNA microarray analysis was undertaken, which identified six discrete clusters of miRNA with characteristic developmental profiles. The functions of predicted target genes for the miRNA in four of the six clusters were enriched for aspects of cell division and regulation of cell proliferation suggesting a potential role of these miRNA in regulating cardiomyocyte proliferation. Conclusion: The results of this study show that the expression of miR-133a and one of its target genes is consistent with it being involved in the suppression of cardiomyocyte proliferation, which occurs across the last third of gestation in sheep. The expression patterns of the miR-15 family, miR-199a and miR-590 were inconsistent with direct involvement in the regulation cardiomyocyte proliferation in sheep, despite studies in rodents demonstrating that their manipulation can influence the degree of cardiomyocyte proliferation. miRNA microarray analysis suggests a coordinated and potentially more complex role of multiple miRNA in the regulation of cardiomyocyte quiescence and highlights significant differences between species that may reflect their substantial differences in the timing of this developmental process. RNA, (2 µg) from three heart samples from each of the 91 d (fetus), 141 d (fetus), 5 d (postnatal) and 173 d (postnatal) groups, was used for analysis according to standard procedures. The experimental design included three biological replicates from each of the four normal developmental ages in sheep and thus a total of 12 samples was analyzed.
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Project description:After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal's lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly.
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