Genome-wide chromatin modification targeting by endogenous small RNAs

内源性小RNA靶向的全基因组染色质修饰

基本信息

批准号：
7830428
负责人：
RONALD P HART
金额：
$ 99.64万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-24 至 2012-08-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics, and specific Challenge Topic 08-CA-104: Regulatory functions of small RNAs. Our goal is to identify small RNAs (smRNAs) as regulators of histone modifying enzymes, mediating interactions with promoters and/or non-coding RNAs present in promoter proximal regions and mediating long-term effects on gene expression. This is a novel model that would tie together genome-encoded small RNAs, non-coding RNAs, and the regulation of histone modifications, leading to long-term modulation of gene expression. Epigenetic modifications are inheritable alterations to the genome in the form of enzymatic manipulations of key histone residues, or the methylation of specific cytosines in the DNA sequence. Carcinogenesis is likely to include aberrant use of this pathway to cause long-term changes in gene expression in transformed cells. In fact, epigenetic dysregulation is a hallmark of numerous cancers, and compounds which broadly affect histone modifications are under intense scrutiny as cancer therapies. While this strategy may be effective, we believe that it will be possible to therapeutically target epigenetic modulation of selected genes by exploiting the existing RNAi machinery, as demonstrated for several smRNAs and genes. This project aims to understand the relationship between small, non-coding RNA sequences and epigenetic histone modifications, and explore the mechanisms by which epigenome-modifying complexes may be recruited by small RNAs to their target DNA sequences. Comparison of smRNAs identified in human embryonic stem cells by deep sequencing with genomic alignment sites and previously published epigenomic data of key histone modifications has identified striking association between these two previously independent pathways. In this proposal we will test the hypothesis that smRNAs mediate the placement of epigenetic marks. Specifically, we will (1) identify and characterize classes of smRNA sequences associated with specific chromatin modifications in human ES Cells during neural differentiation; (2) bioinformatically predict as yet unobserved smRNA-mediated epigenetic effects; and (3) experimentally confirm the functional interaction between small non-coding RNAs and epigenetic modifications in hESC. Epigenetic marking is one of the next great questions in biology and medicine. We propose that endogenous smRNAs are the key link between histone modification mechanisms and individual genomic loci. If smRNAs do in fact direct epigenetic modifications, this may represent a novel mechanism by which cells are capable of transcriptional regulation. This will provide both additional therapeutic targets and enhanced understanding of disease etiologies for regions of altered histone modification during cancers. PUBLIC HEALTH RELEVANCE: Epigenetic dysregulation is a hallmark of several human disorders and numerous cancers. Histone modifications represent one mechanism of epigenetic regulation that directly affects the transcriptional availability of adjacent genomic elements. This project aims to identify the relationship between small, non-coding RNA sequences and epigenetic histone modifications, and explore the mechanisms by which epigenome modifying complexes may be recruited by small RNAs to their target genomic regions. The association of small RNAs with specific histone modifications provides understanding of disease etiologies and suggests mechanisms to transcriptionally regulate target genes in patients.

描述（由申请人提供）：此申请涉及广泛的挑战领域（08）基因组学和特定挑战主题08-CA-104：小型RNA的监管功能。我们的目标是将小的RNA（SMRNA）识别为修饰酶的组蛋白的调节剂，介导启动子近端区域中存在的启动子和/或非编码RNA的相互作用，并介导了对基因表达的长期影响。这是一个新型模型，可以将基因组编码的小RNA，非编码RNA和组蛋白修饰的调节结合在一起，从而导致基因表达的长期调节。表观遗传修饰是对基因组的遗传改变，以关键组蛋白残基的酶促操纵形式，或者在DNA序列中特定胞质的甲基化。癌变可能包括使用该途径的异常使用来导致转化细胞中基因表达的长期变化。实际上，表观遗传失调是众多癌症的标志，并且广泛影响组蛋白修饰的化合物受到癌症疗法的严格审查。尽管该策略可能是有效的，但我们认为，可以通过利用现有的RNAi机械来靶向选定基因的表观遗传调节，如多种SMRNA和基因所证明。该项目旨在了解小的非编码RNA序列与表观遗传组蛋白修饰之间的关系，并探索小RNA可以通过小RNA募集表观遗传组修饰复合物的机制。通过与基因组比对位点进行深度测序和以前发表的关键组蛋白修饰的表观基因组数据的深度测序，对在人类胚胎干细胞中鉴定出的SMRNA进行了比较，已经确定了这两个先前独立的途径之间的惊人关联。在此提案中，我们将测试SMRNA介导表观遗传标记的位置的假设。具体而言，我们将（1）在神经分化过程中识别和表征与人ES细胞中特定染色质修饰相关的SMRNA序列的类别；（2）生物学上预测尚未观察到的SMRNA介导的表观遗传效应；（3）实验证实hESC中小的非编码RNA和表观遗传修饰之间的功能相互作用。表观遗传标记是生物学和医学中的下一个伟大问题之一。我们建议内源性SMRNA是组蛋白修饰机制与单个基因组基因局基因局基因座之间的关键联系。如果SMRNA实际上确实是直接的表观遗传修饰，则可能代表了一种新的机制，可以通过该机制进行转录调节。这将提供额外的治疗靶标，并增强对癌症过程中组蛋白改变区域疾病病因的了解。公共卫生相关性：表观遗传失调是几种人类疾病和众多癌症的标志。组蛋白修饰代表了表观遗传调节的一种机制，该机制直接影响相邻基因组元素的转录可用性。该项目旨在确定小的非编码RNA序列与表观遗传组蛋白修饰之间的关系，并探索小RNA可以通过小RNA募集表观遗传组修饰复合物的机制。小型RNA与特定组蛋白修饰的关联提供了对疾病病因的了解，并提出了转录调节患者靶基因的机制。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

miRNA in pluripotent stem cells.

DOI：
10.2217/rme.10.34
发表时间：
2010-07
期刊：
Regenerative medicine
影响因子：
2.7
作者：
Lakshmipathy U;Davila J;Hart RP
通讯作者：
Hart RP

Cysteine- and glycine-rich protein 1a is involved in spinal cord regeneration in adult zebrafish.

DOI：
10.1111/j.1460-9568.2011.07958.x
发表时间：
2012-02
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Ma L;Yu YM;Guo Y;Hart RP;Schachner M
通讯作者：
Schachner M

Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation.

DOI：
10.1016/j.brainres.2011.12.001
发表时间：
2012-02-03
期刊：
Brain research
影响因子：
2.9
作者：
Pichardo-Casas I;Goff LA;Swerdel MR;Athie A;Davila J;Ramos-Brossier M;Lapid-Volosin M;Friedman WJ;Hart RP;Vaca L
通讯作者：
Vaca L

Transcription factor Sox11b is involved in spinal cord regeneration in adult zebrafish.