New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes
New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes
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DOI：
10.1101/gr.112516.110
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发表时间：
2011-11-01
期刊：
影响因子：
7
通讯作者：
Pedersen, Jakob Skou
中科院分区：
文献类型：
--
作者：
Parker, Brian J.;Moltke, Ida;Pedersen, Jakob Skou
调节RNA结构通常是在基因组中具有多个旁系同源实例的家族成员。家族成员具有相同的功能和结构特性，这使得它们能够作为一个整体进行研究，从而促进生物信息学和实验表征。我们开发了一种比较方法 EvoFam，用于基于一级序列和二级结构相似性对调节 RNA 结构家族进行全基因组鉴定。我们将 EvoFam 应用于 41 路脊椎动物基因组比对。在全基因组范围内，我们鉴定了蛋白质编码区之外的 220 个人类高可信度家族，包含 725 个单独的结构，其中包括 48 个具有已知结构 RNA 元件的家族。已确定的已知家族包括两种非编码 RNA，例如。例如，miRNA 和最近发现的 MALAT1/MEN beta lincRNA 家族；和顺式监管结构，例如。例如，铁反应元素。我们还确定了数十个由强有力的进化证据和其他统计证据（例如 GO 术语丰富）支持的新家族。对于其中一些，详细的分析导致了特定功能假设的制定。例子包括两种假设的自动调节反馈机制：一种涉及 MAT2A 3'-UTR 中的六个长发夹，MAT2A 是产生主要人类甲基供体 S-腺苷甲硫氨酸的关键代谢基因；另一种涉及 tRNA 成熟基因 POP1 内含子中的类似 tRNA 的结构。我们通过实验验证了预测的 MAT2A 结构。最后，我们确定了潜在的新调控网络，包括富含免疫相关基因的短发夹大家族，例如。例如，TNF、FOS 和 CTLA4，其中包括已知的转录物不稳定元件。我们的研究结果例证了转录后调控的多样性，并为进一步表征新的调控机制和非编码 RNA 家族提供了资源。
Regulatory RNA structures are often members of families with multiple paralogous instances across the genome. Family members share functional and structural properties, which allow them to be studied as a whole, facilitating both bio-informatic and experimental characterization. We have developed a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein-coding regions comprising 725 individual structures, including 48 families with known structural RNA elements. Known families identified include both noncoding RNAs, e. g., miRNAs and the recently identified MALAT1/MEN beta lincRNA family; and cis-regulatory structures, e. g., iron-responsive elements. We also identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we identify potential new regulatory networks, including large families of short hairpins enriched in immunity-related genes, e. g., TNF, FOS, and CTLA4, which include known transcript destabilizing elements. Our findings exemplify the diversity of post-transcriptional regulation and provide a resource for further characterization of new regulatory mechanisms and families of noncoding RNAs.