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Role of RNAi components and non-coding RNAs in Chromatin Architecture and Gene Expression Regulation

Dr Muhammad SHUAIB
King Abdullah University Science and Technology (KAUST), Environmental Epigenetics Program, Saudi Arabia

Monday, October 14th 2019 - 2 p.m. - Meeting room 4004, IGBMC
Hosted by Functional genomics and cancer, Ali HAMICHE

Muhammad Shuaib1, Krishna Mohan Parsi2, Manjula Thimma1, Sabir Abdu Adroub1, Taro Mannen4, Tomohiro Yamazaki4, Piero Carninci3, Tetsuro Hirose4, Valerio Orlando1,2

1King Abdullah University Science and Technology (KAUST), Environmental Epigenetics Program, Saudi Arabia. 2IRCSS Fondazione Santa Lucia, Rome, Italy. 3RIKEN Center for Life Science Technologies, Yokohama, Japan. 4Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Short Biosketch: Muhammad earned a BS (Hons) degree in Biotechnology from University of Malakand in 2007, followed by a PhD degree from University of Strasbourg and IGBMC in 2012. In IGBMC under the supervision of Dr. Ali Hamiche, he investigated the role of histone H3 variants, particularly CENP-A, in the epigenetic specification of centromeric chromatin. He continued to stay in IGBMC as a postdoc in Ali Hamiche group till 2014. He moved to King Abdullah University Science and Technology (KAUST) in 2014, where he has been working as a research scientist in the KAUST Environmental Epigenetics Program (KEEP). In KAUST, he has been investigating the role of chromatin-associated RNAi components and long non-coding RNAs in regulating 3D genome organization and gene expression.

Abstract: The role of RNAi in post-transcriptional gene silencing in the cytoplasm is well characterized. Recent reports indicate that RNAi components, especially Argonaute (AGO) proteins, and non-coding RNAs, are present in the nucleus. However, their nuclear function(s), particularly, AGO1 putative nuclear RNA targets and their joint function in the nucleus remain unknown. To uncover the role of AGO1 in the nucleus, we used a combination of genome-wide approaches both in control and AGO1 depleted HepG2 cells. Here, I will present two AGO1 specific nuclear roles, in which we report a novel function linking AGO1 and lncRNAs in controlling nuclear and 3D chromatin architecture. 

First, we found that AGO1 strongly associate with active enhancers, and enhancer RNAs (eRNAs) being produced at those sites. By Hi-C in AGO1 knockdown cells, we observed changes in chromatin organization, including A/B compartment mixing, specifically in AGO1-bound regions. Distinct groups of genes and specially eRNA transcripts located within differentially interacting loci showed altered expression upon AGO1 depletion. Moreover, AGO1 association with enhancer elements is dependent on eRNA transcription. Collectively, our data suggest that enhancer-associated AGO1 contribute to the fine-tuning of chromatin architecture and gene expression in human cells.

Secondly, we identified NEAT1 lncRNA as AGO1 nuclear target. We show that nuclear AGO1 interacts with NEAT1 lncRNA and regulates its expression and paraspeckle formation. NEAT1 is an essential structural component of paraspeckle, a nuclear body involved in multiple functions ranging from gene regulation to development and cancer. Depletion of AGO1 leads to abnormal NEAT1 expression as well as diminished its interaction with critical PSPs, affecting paraspeckles formation. Our data suggest that AGO1 in association with NEAT1 lncRNA can act as a scaffold that bridges chromatin and nuclear bodies in the regulation of genome organization.

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