NIH VideoCast - The 4D Nucleome Project: Epigenome Amplification in Lymphocytes

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The 4D Nucleome Project: Epigenome Amplification in Lymphocytes

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Air date:	Wednesday, February 10, 2016, 4:15:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 353 (56 Live, 297 On-demand)
Category:	Immunology
Runtime:	01:00:46
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	Immunology Interest Group Dr. Rafael Casellas received his Ph.D. in Molecular Immunology from the Rockefeller University in 2002. There, he worked under Dr. Michel Nussenzweig to study the role of immunoglobulin gene expression and recombination in the establishment of B cell tolerance and peripheral activation. From 2002 to 2003 he did postdoctoral training with David Baltimore at the California Institute of Technology, where he continued his studies of B cell activation. In December 2003, Dr. Casellas moved to the Laboratory of Molecular Immunogenetics of NIAMS to create the Genomics & Immunity Group, where he is currently a senior investigator and branch chief. Dr. Casellas is also serving as an adjunct investigator at the Center for Cancer Research, NCI. Rafael’s laboratory is interested in understanding how nuclear events (e.g. transcription, epigenetics, recombination) drive early development and peripheral activation of B lymphocytes. His most important findings include the discovery, together with David Levens (NCI), of transcriptome amplification, a process whereby the transcription program of naïve lymphocytes is globally and proportionally amplified as they engage in the immune response. Rafael’s lab also resolved a long-standing question about the origin of chromosomal translocations in B cell lymphomas. They showed that these genetic aberrations result from promiscuous DNA damage by AID, the immunoglobulin gene mutator, rather than the frequency by which translocating genes interact. Another key finding was that genes expressed in most tissues (e.g. Myc, Pim1) often change their entire enhancer repertoire during development, leading to differential promoter activity. Rafael has organized collaborative projects between intramural and extramural laboratories using the latest technology. In 2011, he established the NIH Mouse Regulome Project, a program that seeks to elucidate how gene expression is regulated in the mouse genome using 3C, genome editing, genomics, and nanoscopy. This dynamic collaboration has so far produced 4 publications in Cell. Currently, the Casellas lab is also contributing to the 4D Nucleome Project, an NIH Director Program that explores the role of nuclear architecture in organismal development. 50 years ago Vincent Allfrey and colleagues discovered that lymphocyte activation promotes histone acetylation and enhances gene expression. Our recent studies confirmed that during stimulation of G0 B cells the transcriptome is globally and proportionally amplified by a mechanism that involves Myc and TFIIH. We have now discovered that B cell chromatin undergoes a comparable amplification in histone acetylation, methylation, and nucleosome remodeling. By means of super-resolution microscopy we have found that this epigenome amplification triggers the spreading of chromatin nanodomains from the periphery to the entire nucleus. Furthermore, nanodomain clusters deconvolute into a mononucleosome fiber by a process that requires ATP synthesis and Myc, and which alters transcription factor dynamics. In stark contrast to quiescent follicular B cells, B-1 and marginal zone-lineage cells display full nanodomain spreading and partial deconvolution. The new data thus reveal key structural and epigenetic changes accompanying cell cycle entry, and help explain the semi-active nature of B lymphocytes constitutively engaged by self-antigens.

NLM Title:	The 4D nucleome project : epigenome amplification in lymphocytes / Rafael Casellas.
Author:	Casellas, Rafael. National Institutes of Health (U.S.). Immunology Interest Group,
Publisher:
Abstract:	(CIT): Our recent studies confirmed that during stimulation of G0 B cells the transcriptome is globally and proportionally amplified by a mechanism that involves Myc and TFIIH. We have now discovered that B cell chromatin undergoes a comparable amplification in histone acetylation, methylation, and nucleosome remodeling. By means of super-resolution microscopy we have found that this epigenome amplification triggers the spreading of chromatin nanodomains from the periphery to the entire nucleus. Furthermore, nanodomain clusters deconvolute into a mononucleosome fiber by a process that requires ATP synthesis and Myc, and which alters transcription factor dynamics. In stark contrast to quiescent follicular B cells, B-1 and marginal zone-lineage cells display full nanodomain spreading and partial deconvolution. The new data thus reveal key structural and epigenetic changes accompanying cell cycle entry, and help explain the semi-active nature of B lymphocytes constitutively engaged by self-antigens.
Subjects:	Epigenomics Gene Amplification--immunology Lymphocytes--immunology
Publication Types:	Lecture Webcast

NLM Classification:	WH 200
NLM ID:	101678432
CIT Live ID:	18374
Permanent link:	https://videocast.nih.gov/watch=18374

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