Some retroviruses, including HIV, insert their DNA in a non-random manner in the host genome through a poorly understood selection mechanism. Here the authors develop a biophysical model of retroviral integration, identifying previously unnoticed universal principles that regulate this phenomenon

A Ballandras-Colas

A Buckle

A Ciuffi

A Dittmore

A Engelman

A Rosa

A Zirkel

AN Boettiger

AT Panganiban

AT Phan

B Marini

CA Brackley

CC Bartholomae

D Jost

D Marenduzzo

D Michieletto

D Pruss

DJ Griffiths

DP Maskell

F Bushman

GA Sowd

GD Bascom

GP Wang

HJ Szerlong

HM Marshall

HP Müller

I Dunham

I Solovei

J Grawenhoff

J Kind

J Matysiak

JR Dixon

K Peng

KA Matreyek

KD Taganov

LA Mirny

M Barbieri

M Benleulmi

M Dewannieux

M Kvaratskhelia

M Lusic

M Naughtin

M Stefano Di

MJ Pace

N Gilbert

N Korfali

ND Jones

P Lesbats

PR Cook

R Craigie

R Garces

R Imai

R Schrijvers

RS Nozawa

S Brahmachari

S Plimpton

SA Grigoryev

SSP Rao

SV Ulianov

SW Sides

T Cremer

T Nagano

T Sexton

VI Risca

YAG Fosado

arXiv

Crossref

Physical principles of retroviral integration in the human genome

Certain retroviruses, including HIV, insert their DNA in a non-random fraction of the host genome via poorly understood selection mechanisms. Here, we develop a biophysical model for retroviral integrations as stochastic and quasi-equilibrium topological reconnections between polymers. We discover that physical effects, such as DNA accessibility and elasticity, play important and universal roles in this process. Our simulations predict that integration is favoured within nucleosomal and flexible DNA, in line with experiments, and that these biases arise due to competing energy barriers associated with DNA deformations. By considering a long chromosomal region in human T-cells during interphase, we discover that at these larger scales integration sites are predominantly determined by chromatin accessibility. Finally, we propose and solve a reaction-diffusion problem that recapitulates the distribution of HIV hot-spots within T-cells. With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection.</jats:p

D. Michieletto

M. Lusic

D. Marenduzzo

E. Orlandini

Physical Principles of Retroviral Integration in the Human Genome

MICHIELETTO, DAMIANO

Lusic, M.

MARENDUZZO, DAVIDE

Orlandini, E.

Archivio istituzionale della ricerca - Università di Padova

English

Certain retroviruses, including HIV, insert their DNA in a non-random fraction of the host genome via poorly understood selection mechanisms. Here, we develop a biophysical model for retroviral integration as stochastic and quasi-equilibrium topological reconnections between polymers. We discover that physical effects, such as DNA accessibility and elasticity, play important and universal roles in this process. Our simulations predict that integration is favoured within nucleosomal and flexible DNA, in line with experiments, and that these biases arise due to competing energy barriers associated with DNA deformations. By considering a long chromosomal region in human T-cells during interphase, we discover that at these larger scales integration sites are predominantly determined by chromatin accessibility. Finally, we propose and solve a reaction-diffusion problem that recapitulates the distribution of HIV hot-spots within T-cells. With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection

Michieletto, D.

Marenduzzo, D.

Edinburgh Research Explorer

Physical Principles of Retroviral Integration in the Human Genome

Abstract

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Crossref

Archivio istituzionale della ricerca - Università di Padova

Edinburgh Research Explorer