Dataset Information

LncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures.

ABSTRACT: Attenuation of pre-rRNA synthesis in response to elevated temperature is accompanied by increased levels of PAPAS ("promoter and pre-rRNA antisense"), a long noncoding RNA (lncRNA) that is transcribed in an orientation antisense to pre-rRNA. Here we show that PAPAS interacts directly with DNA, forming a DNA-RNA triplex structure that tethers PAPAS to a stretch of purines within the enhancer region, thereby guiding associated CHD4/NuRD (nucleosome remodeling and deacetylation) to the rDNA promoter. Protein-RNA interaction experiments combined with RNA secondary structure mapping revealed that the N-terminal part of CHD4 interacts with an unstructured A-rich region in PAPAS. Deletion or mutation of this sequence abolishes the interaction with CHD4. Stress-dependent up-regulation of PAPAS is accompanied by dephosphorylation of CHD4 at three serine residues, which enhances the interaction of CHD4/NuRD with RNA and reinforces repression of rDNA transcription. The results emphasize the function of lncRNAs in guiding chromatin remodeling complexes to specific genomic loci and uncover a phosphorylation-dependent mechanism of CHD4/NuRD-mediated transcriptional regulation.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC6049515 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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lncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures.

Zhao Zhongliang Z Sentürk Nevcin N Song Chenlin C Grummt Ingrid I

Genes & development 20180615 11-12

Attenuation of pre-rRNA synthesis in response to elevated temperature is accompanied by increased levels of PAPAS ("promoter and pre-rRNA antisense")<i>,</i> a long noncoding RNA (lncRNA) that is transcribed in an orientation antisense to pre-rRNA. Here we show that PAPAS interacts directly with DNA, forming a DNA-RNA triplex structure that tethers PAPAS to a stretch of purines within the enhancer region, thereby guiding associated CHD4/NuRD (nucleosome remodeling and deacetylation) to the rDNA ...[more]

PMID: 29907651

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Project description:Cholesterol 7?-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classical pathway of bile acids synthesis in liver and is crucial for maintaining lipid homeostasis. Hepatocyte nuclear factor 4? (HNF4?) and ?1-fetoprotein transcription factor (FTF) are two major transcription factors driving CYP7A1 promoter activity in hepatocytes. Previous researches have shown that Prospero-related homeobox (Prox1) directly interacts with both HNF4? and FTF and potently co-represses CYP7A1 transcription and bile acid synthesis through unidentified mechanisms. In this work, mechanisms involved in Prox1-mediated co-repression were explored by identifying Prox1-associated proteins using immunoprecipitation followed by mass spectrometry (IP-MS) methodology. Multiple components of the epigenetically repressive lysine-specific demethylase 1 (LSD1)/nucleosome remodeling and histone deacetylase (NuRD) complex, most notably LSD1 and histone deacetylase 2 (HDAC2), were found to be associated with Prox1 and GST pulldown assay demonstrated that Prox1 directly interacts with LSD1. Sequential chromatin immunoprecipitation (ChIP) assays showed that Prox1 co-localizes with HNF4?, LSD1 and HDAC2 on CYP7A1 promoter in HepG2 cells. Furthermore, by using ChIP assay on HepG2 cells with endogenous Prox1 knocked down by RNA interference, Prox1 was shown to recruit LSD1 and HDAC2 onto CYP7A1 promoter and cause increased H3K4 demethylation. Finally, bile acids treatment of HepG2 cells, which significantly repressed CYP7A1 transcription, resulted in increased Prox1 and LSD1/NuRD complex occupancy on CYP7A1 promoter with a concurrent increase in H3K4 demethylation and H3/H4 deacetylation. These results showed that Prox1 interacts with LSD1 to recruit the repressive LSD1/NuRD complex to CYP7A1 promoter and co-represses transcription through epigenetic mechanisms. In addition, such Prox1-mediated epigenetic repression is involved in the physiologically essential negative feedback inhibition of CYP7A1 transcription by bile acids.

Dataset Information

LncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures.

Publications

lncRNA PAPAS tethered to the rDNA enhancer recruits hypophosphorylated CHD4/NuRD to repress rRNA synthesis at elevated temperatures.

Similar Datasets

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