Epigenetic regulation of cardiac MHC gene locus

心脏 MHC 基因座的表观遗传调控

基本信息

批准号：
8034233
负责人：
Kenneth M. Baldwin
金额：
$ 47.4万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8034233
关键词：
Acetylation Address Adult Affect Animals Antibodies Antisense RNA Area Binding Sites Biological Assay Budgets CCAAT-Enhancer-Binding Proteins Cardiac Cardiac Myocytes Cell Culture System Cell Culture Techniques Cells Chromatin Chromatin Structure Complex Conserved Sequence Culture Media DNA DNA Methylation DNA-Protein Interaction Deacetylation Development Diabetes Mellitus Epigenetic Process Evolution Functional RNA Funding Gene Expression Gene Expression Regulation Gene Proteins Gene Transfer Genes Genetic Transcription Genomics Goals Grant Guidelines Hamsters Heart Heart Atrium Human Human Resources Hypothyroidism Image Immunoprecipitation In Vitro Intercistronic Region Kidney Liver Maps Measures Messenger RNA Modification Mus Muscle Mutation Myocardium Neonatal Nucleic Acid Regulatory Sequences Oryctolagus cuniculus Pattern Physiological Principal Investigator Process Progress Reports Promoter Regions Property Proteins RNA Rattus Regulation Regulatory Element Reporter Research Reverse Transcriptase Polymerase Chain Reaction Rodent Role Serum Site Skeletal Muscle Small Interfering RNA Soleus Muscle Specific qualifier value Staging Starvation System Technology Thyroid Gland Thyroid Hormones Time Tissues Transcript United States National Institutes of Health Untranslated RNA Western Blotting base bisulfite chromatin immunoprecipitation chromatin remodeling comparative crosslink fetal histone modification in vivo mature animal novel overexpression postnatal pressure programs promoter protein protein interaction research study response tool transcription factor vector young adult

项目摘要

DESCRIPTION (provided by applicant): The antithetical regulation of the cardiac MHC genes (1 and 2) is highly coordinated in response to altered thyroid state, diabetes, pressure overload, and during development, yet the mechanism underlying this regulation is poorly understood. In previous studies, we discovered a naturally occurring antisense 2 RNA transcript that starts in the middle of the intergenic spacer (IGS) between the 2 and 1 genes and extends upstream to the 2MHC gene promoter region, fully overlapping the 2 gene. This antisense transcription originating from the IGS was previously proposed to coordinate cardiac MHC gene expression in normal rodent hearts and in response to altered thyroid state diabetes, and pressure overload. Recently, more comprehensive analyses of intergenic RNA via strand specific RT-PCR revealed the existence of intergenic RNA in the sense direction that is transcribed toward the 1MHC basic promoter region and continues through the 1MHC gene (see figure 1). These results (and preliminary results on promoter reporter assays) strongly support the novel concept that the IGS is transcriptionally active in both directions in rodent heart. Transcription of the lower strand, which proceeds upstream toward the 2MHC gene, produces antisense RNA: a process that may interfere with 2 gene transcription. Transcription of the upper strand, which starts from ~2kb upstream from the 1MHC gene TSS and proceeds through the 1 promoter to within the 1 gene: a process that may enhance 1 gene transcription. Thus, we hypothesize that the intergenic bidirectional transcription controls the coordinated antithetical regulation of adjacent 1 and 2 MHC genes. The goal of this proposed research is to examine the in vivo regulation of the bidirectional intergenic transcription in the context of altering the expression of the two adjacent genes on the cardiac MHC gene locus via an epigenetic mechanism which involves DNA methylation, chromatin remodeling and histone modification. For comparative purposes and as part of our approach to understanding the gene regulation on this locus, studies will also involve the atria and slow skeletal muscle. These tissues are unique in that the former expresses predominantly 1, while the latter expresses only traces of 1, with 2 being predominant. Consequently, this research will explore a new area of gene regulation and investigate an intriguing regulatory mechanism involving non-coding intergenic RNA, and epigenetic regulation of the cardiac MHC gene locus via bidirectional intergenic transcription.

描述（由申请人提供）：心脏 MHC 基因（1 和 2）的对立调节在响应甲状腺状态改变、糖尿病、压力超负荷以及发育过程中高度协调，但这种调节背后的机制知之甚少。在之前的研究中，我们发现了一个天然存在的反义2 RNA转录本，它从2和1基因之间的基因间隔区（IGS）的中间开始，并向上游延伸到2MHC基因启动子区域，与2基因完全重叠。这种源自 IGS 的反义转录先前被认为可以协调正常啮齿动物心脏中的心脏 MHC 基因表达，并响应甲状腺状态改变的糖尿病和压力超负荷。最近，通过链特异性 RT-PCR 对基因间 RNA 进行更全面的分析，揭示了基因间 RNA 在有义方向上的存在，该方向转录至 1MHC 基本启动子区域并继续贯穿 1MHC 基因（见图 1）。这些结果（以及启动子报告基因检测的初步结果）有力地支持了 IGS 在啮齿类动物心脏中双向转录活性的新概念。下链的转录向 2MHC 基因上游进行，产生反义 RNA：这一过程可能会干扰 2 基因转录。上链的转录从 1MHC 基因 TSS 上游约 2kb 处开始，通过 1 启动子进入 1 基因内：这一过程可能会增强 1 基因转录。因此，我们假设基因间双向转录控制相邻 1 和 2 MHC 基因的协调对立调节。这项研究的目的是通过涉及 DNA 甲基化、染色质重塑和组蛋白修饰的表观遗传机制来改变心脏 MHC 基因座上两个相邻基因的表达，从而检查双向基因间转录的体内调节。。出于比较目的，并且作为我们了解该基因座基因调控方法的一部分，研究还将涉及心房和慢骨骼肌。这些组织的独特之处在于前者主要表达 1，而后者仅表达微量的 1，其中 2 占主导地位。因此，本研究将探索基因调控的新领域，并研究涉及非编码基因间RNA的有趣调控机制，以及通过双向基因间转录对心脏MHC基因座进行表观遗传调控。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reverse transcription of the ribonucleic acid: the first step in RT-PCR assay.

核糖核酸的逆转录：RT-PCR 测定的第一步。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Haddad, Fadia;Baldwin, Kenneth M
通讯作者：
Baldwin, Kenneth M

Activity of the beta-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism.

β-肌球蛋白重链反义启动子的活性对糖尿病和甲状腺功能减退症有反应。

DOI：
发表时间：
2007-06
期刊：
影响因子：
0
作者：
Giger, Julia;Qin, Anqi X;Bodell, Paul W;Baldwin, Kenneth M;Haddad, Fadia
通讯作者：
Haddad, Fadia

Intergenic transcription and developmental regulation of cardiac myosin heavy chain genes.

心肌肌球蛋白重链基因的基因间转录和发育调控。

DOI：
发表时间：
2008-01
期刊：
影响因子：
0
作者：
Haddad, Fadia;Qin, Anqi X;Bodell, Paul W;Jiang, Weihua;Giger, Julia M;Baldwin, Kenneth M
通讯作者：
Baldwin, Kenneth M

Potential pitfalls in the accuracy of analysis of natural sense-antisense RNA pairs by reverse transcription-PCR.

通过逆转录 PCR 分析天然有义-反义 RNA 对的准确性存在潜在缺陷。

DOI：
发表时间：
2007
期刊：
影响因子：
3.5
作者：
Haddad, Fadia;Qin, Anqi X;Giger, Julie M;Guo, Hongyan;Baldwin, Kenneth M
通讯作者：
Baldwin, Kenneth M

The CAAT-binding transcription factor 1/nuclear factor 1 binding site is important in beta-myosin heavy chain antisense promoter regulation in rats.

CAAT 结合转录因子 1/核因子 1 结合位点在大鼠 β-肌球蛋白重链反义启动子调节中非常重要。

DOI：
发表时间：
2009-12
期刊：
影响因子：
2.7
作者：
Giger JM;Bodell PW;Baldwin KM;Haddad F
通讯作者：
Haddad F

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Kenneth M. Baldwin其他文献

对等量、延长或缩短模式阻力运动的类似急性分子反应。

DOI：
10.1152/japplphysiol.00776.2006
发表时间：
2007
期刊：
Journal of applied physiology
影响因子：
3.3
作者：
Toni Maria Garma;Cori Ann Kobayashi;F. Haddad;G. R. Adams;P. Bodell;Kenneth M. Baldwin
通讯作者：
Kenneth M. Baldwin