HP1BP3, A Chromatin Retention Factor for Co-Transcriptional MicroRNA Processing
| dc.contributor.advisor | Tu, Benjamin | en |
| dc.contributor.committeeMember | Liu, Qinghua | en |
| dc.contributor.committeeMember | Roth, Michael G. | en |
| dc.contributor.committeeMember | Orth, Kim | en |
| dc.creator | Liu, Haoming | en |
| dc.date.accessioned | 2018-08-24T20:38:04Z | |
| dc.date.available | 2018-08-24T20:38:04Z | |
| dc.date.created | 2016-08 | |
| dc.date.issued | 2016-06-27 | |
| dc.date.submitted | August 2016 | |
| dc.date.updated | 2018-08-24T20:31:38Z | |
| dc.description.abstract | RNA interference (RNAi) is a post-transcriptional gene silencing mechanism found in all eukaryotic organisms. It is characterized by a family of small non-coding RNAs, either endogenous (in the case of microRNAs) or exogenous (in the case of siRNAs), that inhibits gene expression post-transcriptionally. MicroRNAs (miRNAs) are a family of ~21-nt cellular RNAs that govern numerous pathological and physiological processes by mediating translational repression and deadenylation/decay of cognate mRNA. Dysregulation of miRNA expression have been associated with various types of cancer and developmental diseases. Typically, primary (pri-)miRNA transcripts are processed by Drosha complex into precursor (pre-)miRNAs, and then by cytoplasmic Dicer complex into mature miRNAs. The processing of pri-miRNAs is the most highly regulated step in the miRNA biogenesis pathway. Therefore, understanding the molecular mechanisms of pri-miRNA processing and its regulation represents a very important objective in the miRNA filed. Recent studies suggest that the Drosha-DGCR8 complex can be recruited to chromatin to catalyze co-transcriptional processing of primary microRNAs (pri-miRNAs) in mammalian cells. However, the molecular mechanism of co-transcriptional miRNA processing is poorly understood. Here, we find that HP1BP3, a histone H1-like chromatin protein, specifically associates with the Microprocessor and promotes global miRNA biogenesis in HeLa cells. Accordingly, chromatin immunoprecipitation (ChIP) studies reveal genome-wide co-localization of HP1BP3 & Drosha and HP1BP3-dependent Drosha binding to actively transcribed miRNA loci. Moreover, HP1BP3 exhibits a novel pri-miRNA binding activity and promotes the Drosha-pri-miRNA association in vivo. Knockdown of HP1BP3 compromises pri-miRNA processing by resulting in premature release of pri-miRNA transcripts from the chromatin. Taken together, these studies suggest that HP1BP3 promotes co-transcriptional miRNA processing via chromatin retention of nascent pri-miRNA transcripts. This work expands the functional repertoire of the H1 family of proteins and suggests a new concept of chromatin retention factor for widespread co-transcriptional miRNA processing. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1049807570 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/5732 | |
| dc.language.iso | en | en |
| dc.subject | Chromatin | en |
| dc.subject | MicroRNAs | en |
| dc.subject | Nuclear Proteins | en |
| dc.subject | RNA Processing, Post-Transcriptional | en |
| dc.subject | Transcription, Genetic | en |
| dc.title | HP1BP3, A Chromatin Retention Factor for Co-Transcriptional MicroRNA Processing | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Biological Chemistry | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |