近日由美國(guó)賓夕法尼亞大學(xué)醫(yī)學(xué)院皮膚病學(xué)和細(xì)胞發(fā)育生物學(xué)教授Sarah Millar領(lǐng)導(dǎo)的一個(gè)科研小組證實(shí)一對(duì)組蛋白去乙?；福℉istone deacety-lases,HDACs）在哺乳動(dòng)物皮膚的正常形成中發(fā)揮關(guān)鍵性的作用,。研究結(jié)果發(fā)表在Developmental Cell雜志上。
“新發(fā)現(xiàn)不僅揭示了關(guān)于皮膚發(fā)育分子過(guò)程的信息,，還為我們提供了一個(gè)有潛力的抗癌策略：通過(guò)抑制這些HDAC酶從而阻斷那些包含胚胎皮膚相似細(xì)胞的腫瘤的生長(zhǎng),，”Millar說(shuō)。
人體皮膚的最外層又稱為表皮是機(jī)體防止感染和脫水的重要屏障,。表皮是一種復(fù)層結(jié)構(gòu),，表皮最底層的干祖細(xì)胞可不斷分裂以補(bǔ)充最上層隨皮膚脫落而喪失的細(xì)胞。表皮起源于覆蓋在脊椎動(dòng)物胚胎上的表面外胚層,，
Millar研究小組對(duì)表面外胚層變成表皮的機(jī)制非常感興趣,。研究人員決定將研究重點(diǎn)集中到可調(diào)控染色質(zhì)接近性從而控制基因表達(dá)的酶上。在生物中,，染色質(zhì)通常是以核小體為單位組成,，每個(gè)核小體中的DNA都環(huán)繞著一個(gè)組蛋白核心。這一結(jié)構(gòu)的緊密程度可影響基因的表達(dá),。緊密纏繞的染色質(zhì)區(qū)域的基因通常難以接近并受到抑制,，而處于“開放”或“松散”區(qū)域的基因則容易被激活。
組蛋白去乙?；甘且活愒谌旧w的結(jié)構(gòu)修飾和基因表達(dá)調(diào)控發(fā)揮重要作用的蛋白酶,。一般情況下,組蛋白的乙酰化有利于DNA與組蛋白八聚體的解離,，核小體結(jié)構(gòu)松弛,，從而使各種轉(zhuǎn)錄因子和協(xié)同轉(zhuǎn)錄因子能與DNA結(jié)合位點(diǎn)特異結(jié)合，激活基因的轉(zhuǎn)錄,。在細(xì)胞核內(nèi),，組蛋白乙酰化與組蛋白去乙?；^(guò)程處于動(dòng)態(tài)平衡,，并由組蛋白乙酰化轉(zhuǎn)移酶（histone acetyltransferase, HAT）和組蛋白去乙?；腹餐{(diào)控,。HAT將乙酰輔酶A的乙酰基轉(zhuǎn)移到組蛋白氨基末端特定的賴氨酸殘基上,，HDAC使組蛋白去乙?；?，與帶負(fù)電荷的DNA緊密結(jié)合，染色質(zhì)致密卷曲,，基因的轉(zhuǎn)錄受到抑制,。從前的研究表明組蛋白乙酰化作用有可能在表皮發(fā)育中發(fā)揮著重要的作用,，然而對(duì)于其確切功能卻不清楚,。
論文的第一作者賓夕法尼亞大學(xué)的博士生Matthew LeBoeuf在新研究中敲除了小鼠胚胎表面外胚層中的兩個(gè)HDACs基因，發(fā)現(xiàn)當(dāng)缺乏HDAC1和HDAC2時(shí),，表皮不能分化,，并導(dǎo)致胚胎在出生時(shí)死亡。“除了通常我們知道的緊實(shí)染色質(zhì)特殊區(qū)域的功能外,，這些去乙酰酶對(duì)于皮膚發(fā)育也是絕對(duì)必要的,，”Millar說(shuō)。
當(dāng)研究人員檢測(cè)這些突變小鼠時(shí),，發(fā)現(xiàn)這些小鼠除有表皮缺陷,，胚胎亦無(wú)法發(fā)育形成毛囊、舌乳頭,、眼瞼和牙齒等結(jié)構(gòu),，這些缺陷表明還存在另一個(gè)基因p63的缺失。
p63基因是一種可激活或抑制下游基因表達(dá)的轉(zhuǎn)錄因子,。過(guò)去的研究證實(shí)p63可在各種上皮組織的發(fā)育,、分化和形態(tài)發(fā)生上起重要的作用。在新研究中,，LeBoeuf對(duì)p63的下游靶基因的表達(dá)進(jìn)行了檢測(cè),，他發(fā)現(xiàn)p63激活基因在HDAC突變胚胎可正常表達(dá)，然而那些正常情況下受到p63抑制的基因則出現(xiàn)了異常,。LeBoeuf還發(fā)現(xiàn)HDACs可作用于p63抑制基因的上游調(diào)控序列使該區(qū)域的組蛋白去乙?；?/p>
那么,，HDAC突變又是如何導(dǎo)致表皮發(fā)育障礙的呢,？Millar解釋說(shuō)受到p63抑制的基因具有抑制細(xì)胞分裂和誘導(dǎo)細(xì)胞老化的功能。在HDAC突變（p63突變）的細(xì)胞中,，這些細(xì)胞分裂抑制蛋白變得活躍,，通過(guò)抑制祖細(xì)胞層的分裂和自我修復(fù)阻斷表皮發(fā)育。“p63阻斷這些基因表達(dá)是非常重要,，”Millar說(shuō)：“如果其出現(xiàn)異常,，皮膚就無(wú)法正常發(fā)育。”
此外,，Millar研究小組還發(fā)現(xiàn)HDACs還可以抑制p63相關(guān)蛋白p53的活性,。當(dāng)研究人員敲除小鼠中的HDAC時(shí),，阻礙干細(xì)胞增殖的胚胎基因不再受到抑制，其表達(dá)顯著增強(qiáng),。 “新研究結(jié)果表明HDAC抑制劑有可能成為以未分化胚胎樣細(xì)胞為特征的某些皮膚癌的有效治療方法,，“Millar說(shuō)：“目前尚無(wú)這方面的抗腫瘤試驗(yàn)開展，這或許將成為我們未來(lái)的一個(gè)研究方向,。”（生物谷Bioon.com）
生物谷推薦原文出處：
Developmental Cell doi:10.1016/j.devcel.2010.10.015
Hdac1 and Hdac2 Act Redundantly to Control p63 and p53 Functions in Epidermal Progenitor Cells
Authors
Matthew LeBoeuf, Anne Terrell, Sohum Trivedi, Satrajit Sinha, Jonathan A. Epstein, Eric N. Olson, Edward E. Morrisey, Sarah E. MillarSee AffiliationsHint: Rollover Authors and Affiliations Departments of Dermatology and Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Department of Cell and Developmental Biology and the Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Cardiology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Department of Biochemistry, Center for Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA
Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Highlights
Deletion of ectodermal Hdac1/2 blocks epidermal development, phenocopying loss of p63
Targets of Np63-mediated repression are upregulated in Hdac1/2 epidermal mutants
HDACs specifically bind and are active at Np63-repressed promoters
HDAC1/2 are also required to suppress p53 hyperacetylation in embryonic epidermis
Summary
Epidermal and hair follicle development from surface ectodermal progenitor cells requires coordinated changes in gene expression. Histone deacetylases alter gene expression programs through modification of chromatin and transcription factors. We find that deletion of ectodermal Hdac1 and Hdac2 results in dramatic failure of hair follicle specification and epidermal proliferation and stratification, phenocopying loss of the key ectodermal transcription factor p63. Although expression of p63 and its positively regulated basal cell targets is maintained in Hdac1/2-deficient ectoderm, targets of p63-mediated repression, including p21, 14-3-3, and p16/INK4a, are ectopically expressed, and HDACs bind and are active at their promoter regions in normal undifferentiated keratinocytes. Mutant embryos display increased levels of acetylated p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression in keratinocytes. Our data identify critical requirements for HDAC1/2 in epidermal development and indicate that HDAC1/2 directly mediate repressive functions of p63 and suppress p53 activity.
