Control of muscle gene expression by signaling pathways

描述(申请人提供)：这项建议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过程中基因表达的知识空白。阐明染色质结合蛋白破译信号级联传递的信息并将其传播到转录机制的其他组件的分子基础，将揭示选择性药物干预的新靶点，目的是调节基因表达，以影响正常和病理条件下的肌肉生长和再生。在特定的目标1中，我们将研究染色质重塑SWI-SNF复合体如何区分分化激活的p38信号与应激或炎症激活的p38和JNK级联所传递的信息。我们将检验这样一个假设，即SWI/SNF复合体结构亚单位-BAF蛋白-通过分化与应激/炎症激活途径的不同磷酸化模式建立了调节SWI/SNF募集到肌肉基因染色质的密码。在特定的目标2中，我们将阐明肌肉基因调控元件染色质中乙酰基转移酶募集的分子基础，以响应IGF-1引发的促肌原信号。我们将检验一种假设，即AKT介导的位于乙酰基转移酶p300 C/H3区域的特定残基的磷酸化促进了与肌肉调节因子MyoD的相互作用。在特定的目标3中，我们将研究SWI/SNF对在分化过程中沉默的增殖基因启动子的招募是否也受p38途径的指导。我们还将研究分化激活的p38的细胞抑制活性将IGF1激活的信号通路从有丝分裂信号转化为促肌信号的机制。我们将利用在特定目标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信号之间的功能相互依赖。这项研究将加深我们对肌肉形成、生长和再生过程中Sjgnal转导通路调节基因表达的分子机制的了解。从这项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物策略的新靶点，以选择性地调节神经肌肉疾病和其他伴随肌肉丧失的病理疾病的基因表达，如癌症相关的恶病质和衰老相关的石棺减少。

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.