Control of muscle gene expression by signaling pathways

描述（由申请人提供）：本提案的总体目标是填补关于细胞内信号通路如何将环境提示转化为染色质修饰以调节肌肉分化期间基因表达的知识空白差距。通过信号级联传递的信息被染色质结合蛋白破译并广播到转录机制的其他组分的分子基础的阐明，将揭示旨在调节基因表达以影响正常和病理条件下肌肉生长和再生的选择性药理学干预的新靶点。在具体目标1中，我们将研究染色质重塑SWI-SNF复合物如何区分由分化激活的p38信号传导与应激或炎症激活的p38和JNK级联传递的信息。我们将测试的假设，不同的磷酸化模式的SWI/SNF复合物的结构亚单位-BAF蛋白-通过分化-与压力/炎症-激活的途径建立的代码，调节SWI/SNF招募到肌肉基因的染色质。在具体的目标2，我们将阐明乙酰转移酶招聘的肌肉基因调控元件的染色质的分子基础，以响应促肌细胞生成信号引起的IGF-1。我们将测试的假设，AKT介导的磷酸化的特定残基位于C/H3区域内的乙酰转移酶p300，促进与肌肉调节因子MyoD的相互作用。在具体目标3中，我们将研究SWI/SNF向在分化期间沉默的增殖基因的启动子的募集是否也由p38途径指导。我们还将研究分化激活的p38的细胞生长抑制活性将IGF 1激活的途径从促有丝分裂信号传导转化为促肌生成信号传导的机制。我们将利用特定目标1和2中产生的信息和试剂，在染色质水平上研究p38通路和PiSK/AKT信号传导之间的功能相互依赖性。本研究将进一步加深我们对信号转导通路在肌肉形成、生长和再生过程中调控基因表达的分子机制的认识。从该提案中收集的结果将对再生医学产生影响，因为它们最终将揭示药理学策略的新目标，以选择性地调节神经肌肉疾病和其他伴随肌肉损失的病理状况的基因表达，例如癌症相关的恶病质和衰老相关的肌肉减少症。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to fill the gap of knowledge on how intra-cellular signaling pathways convert environmental cues into chromatin modifications to regulate gene expression during muscle differentiation. The elucidation of the molecular basis by which the information transmitted by signaling cascades is deciphered by chromatin-binding proteins and broadcasted to other components of the transcription machinery will reveal new targets for selective pharmacological interventions aimed at modulating gene expression to influence muscle growth and regeneration in normal and pathological conditions. In specific aim 1, we will investigate how the chromatin remodeling SWI-SNF complex discriminates between the information transmitted by the differentiation-activated p38 signaling vs stress- or inflammation- activated p38 and JNK cascades. We will test the hypothesis that distinct phosphorylation patterns of the structural sub-units of the SWI/SNF complex - the BAF proteins - by differentiation- vs stress/inflammation- activated pathways establish the code that regulates SWI/SNF recruitment to the chromatin of muscle genes. In specific aim 2, we will elucidate the molecular basis of acetyltransferase recruitment to the chromatin of muscle-gene regulatory elements in response to the pro-myogenic signaling elicited by IGF-1. We will test the hypothesis that AKT-mediated phosphorylation of specific residues located within the C/H3 region of the acetyltransferase p300, promotes the interaction with the muscle regulatory factor MyoD. In specific aim 3, we will investigate whether the recruitment of SWI/SNF to the promoters of proliferation genes, which are silenced during differentiation, is also directed by the p38 pathway. We will also study the mechanism by which the cytostatic activity of differentiation-activated p38 converts the IGF1-activated pathway from a mitogenic to a pro-myogenic signaling. We will take advantage from information and reagents generated in specific aims 1 and 2 to study the functional interdependence between the p38 pathway and the PiSK/AKT signaling at the chromatin level. This study will improve our knowledge on the molecular mechanism by which sjgnal transduction pathways regulate gene expression during muscle formation, growth and regeneration. The results gathered from this proposal will have an impact on regenerative medicine, as they will eventually reveal new targets for pharmacological strategies to selectively modulate gene expression in the therapy of neuromuscular disorders and other pathological conditions accompanied by muscle loss, such as cancer-associated cachexia and aging-associated sarcopenia.