The Tails of Two Histones: It was an old histone, it was a new histone

Stem cell;histone;epigenetic;Cell Biology

Tran, VuongChen, Xin ;

Johns Hopkins University

关键词: Stem cell;    histone;    epigenetic;    Cell Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/36973/TRAN-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The basis of multi-cellular systems relies on different cell types performing different roles for a properly functioning organism.However, these cells need to express different sets of genes in order to maintain their different identities while using a common genome.This phenomenon can be resolved in the context of proteins such as histones that can bind to genomic DNA and are modified post-translationally to regulate gene expression. As such, the inheritance and maintenance of distinct chromatin state may contribute to determine and maintain cell identity.Inheritance of chromatin profile after successive cell divisions is substantial for epigenetic regulation. Among all cell types, stem cells remain one of the most critical populations for maintaining homeostasis.If the ability of stem cells to maintain their identity is compromised, it will result in stem cell loss, which would eventually lead to tissue degeneration.Conversely, if that the progeny cells derived from stem cells cannot differentiate into specific cell types, but rather keep on dividing, it may lead to tumorigenesis.My thesis project aims to understand how differential histone inheritance is related to stem cell identity. I found that in the Drosophila male germline stem cell (GSC) system, pre-existing H3 histones are preferentially segregated to the stem cell during asymmetric germline stem cell division. Based on this finding, we propose a two-step model to explain the asymmetric histone distribution: (1) prior to mitosis, preexisting histones and newly synthesized histones are differentially distributed at two sets of sister chromatids; (2) during mitosis, the set of sister chromatids with preexisting histones are segregated to GSCs while the other set of sister chromatids with newly synthesized histones are partitioned to the daughter cell committed for differentiation.Whether this phenomenon contributes to maintain stem cell identity and to reset chromatin structure in the other daughter cell for differentiation remains to be determined. In addition to our findings on histone asymmetry in germline stem cell, we also explore how histone contributes to differentiating germ cell identity. Asymmetric stem cell division yields two daughter cell.Since one daughter remains a stem cell, the other daughter is the gonialblast that go on to mitotically expand into spermatogonial cysts, differentiate into spermatocytes, and consequently form functional sperms. The transitions from spermatogonia to spermatocytes and then to spermatids are regulated in a step-wise manner.Differentiation gene expression is repressed in spermatogonia.Whencells transit to the spermatocyte stage genes are turned on in a coordinated manner.The Polycomb Group (PcG) protein is a class of proteins that maintain the repressed state of genes through epigenetic silencing in spermatogenesis.This is largely done through modification of histone tails.In order for differentiation to proceed, PcG function needs to be counteracted.This requires function of the testis-specific Meiotic Arrest Complex (tMAC) and the testis-specific TATA-binding protein Associated Factors (tTAFs), which antagonizes PcG repressive function.In this thesis we will examine how these complexes contribute to germ cell differentiation through regulation of the chromatin landscape.