Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes

The importance of understanding the molecular mechanisms of murine leukemia virus (MLV) integration into host chromatin is highlighted by the development of MLV-based vectors for human gene-therapy. We have recently identified BET proteins (Brd2, 3 and 4) as the main cellular binding partners of MLV...

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Main Authors:	Larue, Ross C., Plumb, Matthew R., Crowe, Brandon L., Shkriabai, Nikoloz, Sharma, Amit, DiFiore, Julia, Malani, Nirav, Aiyer, Sriram S., Roth, Monica J., Bushman, Frederic D., Foster, Mark P., Kvaratskhelia, Mamuka
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005663/

id	pubmed-4005663
recordtype	oai_dc
spelling	pubmed-40056632014-05-01 Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes Larue, Ross C. Plumb, Matthew R. Crowe, Brandon L. Shkriabai, Nikoloz Sharma, Amit DiFiore, Julia Malani, Nirav Aiyer, Sriram S. Roth, Monica J. Bushman, Frederic D. Foster, Mark P. Kvaratskhelia, Mamuka Gene Regulation, Chromatin and Epigenetics The importance of understanding the molecular mechanisms of murine leukemia virus (MLV) integration into host chromatin is highlighted by the development of MLV-based vectors for human gene-therapy. We have recently identified BET proteins (Brd2, 3 and 4) as the main cellular binding partners of MLV integrase (IN) and demonstrated their significance for effective MLV integration at transcription start sites. Here we show that recombinant Brd4, a representative of the three BET proteins, establishes complementary high-affinity interactions with MLV IN and mononucleosomes (MNs). Brd4(1–720) but not its N- or C-terminal fragments effectively stimulate MLV IN strand transfer activities in vitro. Mass spectrometry- and NMR-based approaches have enabled us to map key interacting interfaces between the C-terminal domain of BRD4 and the C-terminal tail of MLV IN. Additionally, the N-terminal fragment of Brd4 binds to both DNA and acetylated histone peptides, allowing it to bind tightly to MNs. Comparative analyses of the distributions of various histone marks along chromatin revealed significant positive correlations between H3- and H4-acetylated histones, BET protein-binding sites and MLV-integration sites. Our findings reveal a bimodal mechanism for BET protein-mediated MLV integration into select chromatin locations. Oxford University Press 2014-04 2014-02-11 /pmc/articles/PMC4005663/ /pubmed/24520112 http://dx.doi.org/10.1093/nar/gku135 Text en © The Author(s) 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Larue, Ross C. Plumb, Matthew R. Crowe, Brandon L. Shkriabai, Nikoloz Sharma, Amit DiFiore, Julia Malani, Nirav Aiyer, Sriram S. Roth, Monica J. Bushman, Frederic D. Foster, Mark P. Kvaratskhelia, Mamuka
spellingShingle	Larue, Ross C. Plumb, Matthew R. Crowe, Brandon L. Shkriabai, Nikoloz Sharma, Amit DiFiore, Julia Malani, Nirav Aiyer, Sriram S. Roth, Monica J. Bushman, Frederic D. Foster, Mark P. Kvaratskhelia, Mamuka Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
author_facet	Larue, Ross C. Plumb, Matthew R. Crowe, Brandon L. Shkriabai, Nikoloz Sharma, Amit DiFiore, Julia Malani, Nirav Aiyer, Sriram S. Roth, Monica J. Bushman, Frederic D. Foster, Mark P. Kvaratskhelia, Mamuka
author_sort	Larue, Ross C.
title	Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
title_short	Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
title_full	Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
title_fullStr	Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
title_full_unstemmed	Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
title_sort	bimodal high-affinity association of brd4 with murine leukemia virus integrase and mononucleosomes
description	The importance of understanding the molecular mechanisms of murine leukemia virus (MLV) integration into host chromatin is highlighted by the development of MLV-based vectors for human gene-therapy. We have recently identified BET proteins (Brd2, 3 and 4) as the main cellular binding partners of MLV integrase (IN) and demonstrated their significance for effective MLV integration at transcription start sites. Here we show that recombinant Brd4, a representative of the three BET proteins, establishes complementary high-affinity interactions with MLV IN and mononucleosomes (MNs). Brd4(1–720) but not its N- or C-terminal fragments effectively stimulate MLV IN strand transfer activities in vitro. Mass spectrometry- and NMR-based approaches have enabled us to map key interacting interfaces between the C-terminal domain of BRD4 and the C-terminal tail of MLV IN. Additionally, the N-terminal fragment of Brd4 binds to both DNA and acetylated histone peptides, allowing it to bind tightly to MNs. Comparative analyses of the distributions of various histone marks along chromatin revealed significant positive correlations between H3- and H4-acetylated histones, BET protein-binding sites and MLV-integration sites. Our findings reveal a bimodal mechanism for BET protein-mediated MLV integration into select chromatin locations.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005663/
_version_	1612083997640228864

Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes

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