Phosphoproteomics Reveals the AMPK Substrate Network in Response to DNA Damage and Histone Acetylation

AMP-activated protein kinase(AMPK) is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates. Emerging studies have demonstrated the regulatory roles of AMPK in DNA repair, but the underlying mechanisms remain to be fully understood. Herein, using mass spectrometry-based proteomic technologies, we systematically investigate the regulatory network of AMPK in DNA damage response(DDR). Our system-wide phosphoproteome study uncovers a variet...     

JDP2:一种参与组蛋白乙酰化的转录因子

Jun二聚化蛋白-2（Jun dimerization protein-2,JDP2）是转录因子复合体AP-1的抑制性组分。JDP2能形成同源二聚体或与c-Jun、JunB、JunD、ATF-2等形成异源二聚体,抑制AP-1的转录激活作用。同时JDP2还能募集组蛋白去乙酰基酶,或直接与组蛋白结合,抑制组蛋白的乙酰化,通过改变染色质结构调控基因转录。JDP2通过在DNA、染色质多个水平调控基因的转录,在细胞的多种生理或病理活动中发挥着重要作用。     

组蛋白乙酰化/去乙酰化与基因表达调控

组蛋白是真核生物染色质的主要成分,组蛋白修饰(如甲基化、乙酰化、磷酸化、泛素化等)在真核生物基因表达调控中发挥着重要的作用.在这些修饰中,组蛋白乙酰化/去乙酰化尤为重要.组蛋白乙酰化/去乙酰化可通过改变染色质周围电荷或参与染色质构型重建而影响基因表达;更重要的是组蛋白乙酰化/去乙酰化可形成一种特殊的“密码”,被其它蛋白质识别,影响多种蛋白质因子的活动或与其相互作用,参与到基因表达调控的整个网络中.     

组蛋白乙酰化／去乙酰化作用与真核基因转录调控

核小体组蛋白的翻译后修饰是真核基因转录调控中的关键步骤。对于组蛋白的这类修饰方式 ,近年来研究最为活跃的是组蛋白Ｎ末端区域保守的Ｌｙｓ上ε ＮＨ 3 的乙酰化作用。随着各种组蛋白乙酰化酶 /去乙酰化酶被克隆、鉴定 ,组蛋白乙酰化 /去乙酰化作用与真核基因转录调控之间的关系也开始逐步得以阐明。1 .真核转录相关的组蛋白乙酰化酶和组蛋白去乙酰化酶1 .1　组蛋白乙酰化酶 (ｈｉｓｔｏｎｅａｃｅｔｙｌｔｒａｎｓ ｆｅｒａｓｅ ,ＨＡＴ)　　核小体组蛋白中Ｎ末端区域上保守的Ｌｙｓ的乙酰化是染色质具有转录活性的标志之一。在组蛋白…     

组蛋白乙酰化/去乙酰化在真核基因转录调控中的作用

真核生物中 ,染色质的基本单位是核小体。核小体由H2 A ,H2 B ,H3 ,H4构成的核心组蛋白八聚体及缠绕于其上的DNA构成。最近的研究结果表明 ,核心组蛋白的乙酰化 去乙酰化过程是调控基因活性的一个关键步骤[1] 。而含有组蛋白去乙酰化酶活性的分子有两类 :一类是与酵母RPD3同源的分子 ,另一类是与RPD3不同源的分子。它们各有其不同的来源 ,存在于各自的复合物中 ,催化不完全相同的组蛋白或其他蛋白质去乙酰化 ;这些去乙酰化酶与基因转录的调控存在着密切的关系 ,主要是介导基因转录的抑制。     

System-Wide Analysis Reveals a Complex Network of Tumor-Fibroblast Interactions Involved in Tumorigenicity

Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.     

组蛋白甲基化与乙酰化的研究进展

组蛋白甲基化与乙酰化作为共价修饰的两种不同方式,参与许多生物学过程,并在基因表达调控中有重要作用.探讨组蛋白甲基化、乙酰化以及二者之间的关系,对认识疾病相关基因功能有重要意义,并可进一步了解基因转录的表观遗传学调控机制.     

Dietary Resistant Starch Reduces Histone Acetylation on the Glucose-Dependent Insulinotropic Polypeptide Gene in the Jejunum

We have reported that dietary resistant starch (RS) reduces glucose-dependent insulinotropic polypeptide (GIP) mRNA levels along the jejunoileum in both normal and diabetic rats. In this study, we found that jejunal reduction of the GIP gene by feeding normal rats dietary RS was associated with decreases in histone H3 and H4 acetylation on the promoter/enhancer region of the gene.     

TFIIIC Binding to Alu Elements Controls Gene Expression via Chromatin Looping and Histone Acetylation

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Trrap-Dependent Histone Acetylation Specifically Regulates Cell-Cycle Gene Transcription to Control Neural Progenitor Fate Decisions

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组蛋白乙酰化在转录调节中的作用

组蛋白乙酰化对染色质结构有重要影响,与特定位点的基因活化有直接联系,是转录调节的重要方式,在细胞生长、分化、衰老过程中起重要作用.