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Genetic and epigenetic mechanisms of developmental gene regulation

发育基因调控的遗传和表观遗传机制

基本信息

批准号：
10623577
负责人：
Daniel J McKay
金额：
$ 45.83万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-05-31
项目状态：
未结题

项目摘要

Project Summary/Abstract Nearly all cells in our bodies contain the same genome, and thus each of them has the capacity to adopt one of many cell identities. Normal development is characterized by progressive restriction in cell identity from multipotent progenitor cells toward terminally differentiated cells. Most cells choose a single identity and maintain it over time. However, defects in cell fate determination or maintenance can allow cells to escape the restrictions on cell identity, endowing them with new properties that cause disease. For this reason, the steps leading to disease have been described as development gone awry. More importantly, it suggests that cells proceed down the path to disease by inappropriately accessing genetic information controlling cell identity. Thus, studying the mechanisms controlling access to genetic information during normal development can inform how deregulation of these mechanisms contributes to disease. My lab studies two different regulatory layers controlling access to DNA-encoded information and their importance in controlling gene expression. Research during the term of this grant will interrogate the mechanisms underlying (1) how chromatin-based packaging of transcriptional enhancers determines where and when transcription factors bind DNA to switch genes on or off, and (2) how modifications of histone proteins contribute to chromatin organization and transcriptional control. DNA is wrapped around histone proteins to form nucleosomes, the repeating unit of chromatin. Nucleosomes are barriers to transcription factor binding, inhibiting early steps of gene activation. Thus, understanding how chromatin is made accessible to transcription factors is necessary for understanding gene control. More importantly, returning open chromatin to a closed state and reinstating this barrier is critical for preventing gene activation at the wrong time or place. However, the mechanisms controlling chromatin closing are uncharacterized. We have uncovered a temporal cascade of transcription factors, which we term “chromatin gatekeepers” due to their requirement for opening and closing access to enhancers, that we study to decipher these mechanisms. We will also investigate how information about decisions made earlier in development is propagated over time. A key to unlocking this question is a unique genetic resource we recently generated that enables us to directly test the function of histones. Histones are subject to a diverse array of post-translational modifications (PTMs) that are thought to carry epigenetic information to control DNA-templated processes, including transcription. However, evidence supporting the role of histone PTMs in animals is largely correlative due to the difficulty in creating mutant histone genotypes in animals. Drosophila is distinct among animal models in that the histone genes reside at a single locus in the genome. We can replace the endogenous histone genes with tailor-made versions, thereby providing us with the first opportunity to distinguish between regulatory information that is directly encoded in the DNA sequence and information that is epigenetically propagated. We will employ this approach to interrogate the role that histone PTMs play in transcriptional regulation and in control of 3D genome organization.

项目摘要/摘要我们体内的几乎所有细胞都含有相同的基因组，因此它们中的每一个都有能力采用其中一个很多手机的身份。正常发育的特征是细胞身份的进行性限制多能祖细胞向终末分化细胞分化。大多数细胞选择单一的身份并保持随着时间的推移。然而，细胞命运确定或维护方面的缺陷可能会使细胞逃脱限制在细胞身份上，赋予它们导致疾病的新特性。出于这个原因，导致疾病被描述为发育出了问题。更重要的是，它表明细胞向下通过不适当地获取控制细胞身份的遗传信息而导致疾病的途径。因此，研究在正常发育过程中控制获得遗传信息的机制可以为放松管制提供信息这些机制中的任何一个都会导致疾病。我的实验室研究了控制访问的两个不同的规章层 DNA编码信息及其在控制基因表达中的重要性。在此期间进行的研究格兰特将询问潜在的机制(1)基于染色质的包装转录增强子决定转录因子何时何地与DNA结合以开启或关闭基因，以及(2)如何组蛋白的修饰有助于染色质的组织和转录控制。DNA被包裹起来了围绕组蛋白形成核小体，核小体是染色质的重复单位。核小体是阻碍转录因子结合，抑制基因激活的早期步骤。因此，了解染色质是如何形成的转录因子的可及性对于理解基因控制是必要的。更重要的是，重新开放染色质进入封闭状态并恢复这一屏障对于防止基因在错误的时间激活至关重要或地点。然而，控制染色质关闭的机制尚不清楚。我们发现了一个转录因子的时间级联，我们称之为“染色质守门人”，因为它们需要开放和关闭对增强剂的访问，我们研究这些机制以解密这些机制。我们还将调查关于开发早期决策的信息是如何随着时间的推移传播的。一把解锁这把钥匙问题是我们最近产生的一种独特的遗传资源，它使我们能够直接测试组蛋白。组蛋白受到多种翻译后修饰(PTM)的影响，这些修饰被认为是携带表观遗传信息以控制DNA模板化过程，包括转录。然而，有证据表明支持组蛋白PTMS在动物中的作用在很大程度上是相关的，因为创建突变的组蛋白是困难的动物的基因分型。果蝇在动物模型中的不同之处在于组蛋白基因位于单一的基因组中的基因座。我们可以用量身定制的版本来取代内源性的组蛋白基因，从而提供美国第一次有机会区分直接编码在DNA中的监管信息从表观遗传上传播的序列和信息。我们将使用这种方法来审问这个角色组蛋白PTMS在转录调控和3D基因组组织控制中发挥作用。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disentangling the developmental origins of a novel phenotype: enhancement versus reversal of environmentally induced gene expression

解开新表型的发育起源：环境诱导的基因表达的增强与逆转

DOI：
10.1098/rspb.2022.1764
发表时间：
2022
期刊：
Proceedings of the Royal Society B: Biological Sciences
影响因子：
0
作者：
Levis, Nicholas A.;McKay, Daniel J.;Pfennig, David W.
通讯作者：
Pfennig, David W.

Supramolecular assembly of the beta-catenin destruction complex and the effect of Wnt signaling on its localization, molecular size, and activity in vivo.

DOI：
10.1371/journal.pgen.1007339
发表时间：
2018-04
期刊：
PLoS genetics
影响因子：
4.5
作者：
Schaefer KN;Bonello TT;Zhang S;Williams CE;Roberts DM;McKay DJ;Peifer M
通讯作者：
Peifer M

Advancements in mapping 3D genome architecture.

DOI：
10.1016/j.ymeth.2019.06.002
发表时间：
2020-01
期刊：
Methods
影响因子：
4.8
作者：
D. J. McKay;Alexis V. Stutzman;Jill M. Dowen
通讯作者：
D. J. McKay;Alexis V. Stutzman;Jill M. Dowen

Distinct roles for canonical and variant histone H3 lysine-36 in Polycomb silencing.

DOI：
10.1126/sciadv.adf2451
发表时间：
2023-03
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Salzler, Harmony R.;Vandadi, Vasudha;McMichael, Benjamin D.;Brown, John C.;Boerma, Sally A.;Leatham-Jensen, Mary P.;Adams, Kirsten M.;Meers, Michael P.;Simon, Jeremy M.;Duronio, Robert J.;McKay, Daniel J.;Matera, A. Gregory
通讯作者：
Matera, A. Gregory

Centrosome Loss Triggers a Transcriptional Program To Counter Apoptosis-Induced Oxidative Stress.

中心体丢失触发转录程序来对抗细胞凋亡诱导的氧化应激。