During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. We sought to elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene after treatment with serum or the α-adrenergic agonist phenylephrine. Depletion of Bmal1 decreased the expression of clock-controlled genes and , as well as , a Bmal1 target upregulated in adult embryonic hearts. Bmal1 knockdown impaired and promoter accessibility as measured by micrococcal nuclease-quantitative PCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting natriuretic peptide B transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented phenylephrine-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the promoter. represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

中文翻译：

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心脏发育和生长过程中组蛋白周转的昼夜节律控制


在出生后心脏肥大期间，心肌细胞经历有丝分裂退出，依靠 DNA 复制独立的组蛋白周转机制来维持染色质组织和基因转录。在其他组织中，核小体占据的昼夜节律振荡影响时钟控制的基因表达，表明生物钟在组蛋白周转的时间控制和协调心肌细胞基因表达中发挥作用。我们试图阐明主要昼夜节律转录因子 Bmal1 在组蛋白更新、染色质组织以及新生儿期心肌细胞特异性基因表达和细胞生长中的作用。在用血清或 α-肾上腺素能激动剂去氧肾上腺素治疗后，新生大鼠心室肌细胞中的 Bmal1 敲低会降低心肌细胞大小、细胞总蛋白合成和胎儿肥大基因的转录。 Bmal1 的缺失会降低生物钟控制基因的表达，并且 Bmal1 靶点在成人胚胎心脏中上调。通过微球菌核酸酶定量 PCR 测量，Bmal1 敲低损害了启动子的可及性，并且通过酸溶性染色质组分的代谢标记测量，组蛋白周转受损。 Sik1 敲除反过来又减少了肌细胞大小，同时抑制利尿钠肽 B 转录并激活 Per2 转录。将这些变化与染色质重塑联系起来，复制独立组蛋白变体 H3.3a 的耗竭抑制了心肌细胞肥大，并阻止了去氧肾上腺素诱导的时钟控制基因转录的变化。 Bmal1 是新生儿肌细胞生长、复制无关的组蛋白更新和启动子处染色质组织所必需的。 代表一种新型时钟控制基因，可协调肌细胞生长与肥大和时钟控制基因转录。心肌细胞中时钟控制基因响应生长刺激的转录重塑需要不依赖于复制的组蛋白周转。