迈克尔·科斯格罗夫博士

研究抽象

结构生物学 of Chromatin, Epigenetics

The fundamental repeating unit of chromatin, 的核小体, is composed of a disc-shaped octamer of histone proteins around which is wrapped approximately 150-base pairs of genomic DNA. Nucleosomes regulate access to genes by forming a steric block to transcription factors and RNA polymerase. Less clear is how nucleosome positioning on DNA is regulated. Recent studies show that nucleosomes are strategically positioned throughout genomes, that even subtle changes in nucleosome positioning can have profound effects on gene expression. These results raise the possibility that alterations in nucleosome positioning could result in heritable silencing of genes, the generation of new forms and functions at the organismal level. Such alterations are independent of changes in DNA sequence (i.e., epigenetic alterations) and may be another source of variation acted upon by natural selection. An understanding of this process requires an understanding of how cells encode nucleosome positioning information, how that information is inherited. The keys to this process are the evolutionarily conserved histone proteins, the building blocks of nucleosomes; which, 像DNA一样, are semi-conserved during DNA replication. Posttranslational modifications of histones provide a potential vehicle for the heritable transmission of epigenetic traits. Understanding how this process works is one of the central questions in biology today.

We are working to understand the molecular mechanisms that regulate methylation of histone H3 lysine 4 (H3K4), an epigenetic mark required for inheritance of transcriptionally active states of chromatin. 在人类, H3K4 methylation is catalyzed by the 混合系白血病 (MLL) group of enzymes, mutations of which are associated with leukemias, 实体肿瘤, 以及发育异常. We use the tools of structural biology, biochemistry and biophysics to understand the molecular mechanisms for how the family of MLL enzymes work. We place an emphasis on understanding MLL’s function within the context of a large multi-subunit complex, 称为MLL1核心复合体. We have discovered that one of the components the MLL1 core complex is a novel histone methyltransferase we call WRAD, that catalyzes dimethylation within the complex. This finding changes the paradigm for our understanding of how multiple methylation is regulated within cells, which has profound implications for control of gene expression. Our studies on the structure and enzymology of MLL family enzymes will provide insights into their roles in cancer and developmental disorders, provide the basis for the rational drug development of new treatments to help alleviate human suffering.

Projects are available to study the structure and enzymology of MLL family enzymes and the proteins with which they interact, using techniques such as X-ray crystallography, 小角x射线散射, 分析超速离心法, enzyme kinetics and rational drug design.

更多信息请参见: http://www.cosgrovelab.org

选择参考:

Mayse L.A.伊姆兰，A.Karimi, G., •. M.S., 乌尔夫,.J.莫维利亚努，L. (2022). Disentangling the recognition complexity of a protein hub using a nanopore. 自然通讯 (接受).

亚瑟,E.T. Namitz K.E.W., •M.S., 肖沃尔特,年代.A. (2021) Probing multiple methylations events in real time with NMR spectroscopy. 生物物理期刊 120 (21), 4710-4721.

伊姆兰,.莫耶，B.S.坎宁，A.J.卡莉娜，D.邓肯，T。.M.穆迪，K.J.沃尔夫，A.J., •M.S., 和莫维利亚努，L. (2021) Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions. 生物化学杂志 478, 2145-2161.

Namitz K.E.W.*，郑，T.坎宁，A.J.艾丽西亚-委拉斯开兹，n.n.C .卡斯特纳达.A.**, •M.S.**哈内斯，S.D.** (2021) Structural analysis suggests Ess1 isomerizes the carboxy-terminal domain of RNA polymerase II via a bivalent anchoring mechanism. 通信生物学 4, 398. (*co-first authors, **co-corresponding authors)

赵,我.布莱尼，A.刘，X.， Jin, W. 燕,我.哈，J.甘迪，L.坎宁，A.J.康纳利，M.，杨，C.刘，X.，肖，Y., •M.S.索尔马兹，S.R.张，Y.,禁止. D.陈杰.， Loh, S.N.Wang, C. (2021) EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction. 自然通讯 12, 986.

廖,我.艾丽西亚-委拉斯开兹，n.n.L.朗拜，L.，牛，X.蔡伟.， Cho, E.张，M.德布勒，E.闫琦., •M.S.*, 杨，H.* (2019). High affinity binding of H3K14ac through collaboration of bromodomains 2, 3, 5 is critical to the molecular and tumor suppressor functions of PBRM1. 分子肿瘤学 13, 811-823. *(共同通讯作者)

Alicea-Velazquez N.L.辛斯基，S.A.， Loh, D. M.李，J.H.斯卡尔尼克，D.G., •M.S. (2016). Targeted disruption of the interaction between WD-40 repeat protein-5 (WDR5) and 混合系白血病 (MLL/SET1) family proteins specifically inhibits MLL1 and SETd1A methyltransferase complexes. 生物化学杂志 291, 22357-22372.