@article{2570d9c091ec4b659dc5a667222f9a9b,
title = "Synthetic regulatory reconstitution reveals principles of mammalian Hox cluster regulation",
abstract = "Precise Hox gene expression is crucial for embryonic patterning. Intra-Hox transcription factor binding and distal enhancer elements have emerged as the major regulatory modules controlling Hox gene expression. However, quantifying their relative contributions has remained elusive. Here, we introduce “synthetic regulatory reconstitution,” a conceptual framework for studying gene regulation, and apply it to the HoxA cluster. We synthesized and delivered variant rat HoxA clusters (130 to 170 kilobases) to an ectopic location in the mouse genome. We found that a minimal HoxA cluster recapitulated correct patterns of chromatin remodeling and transcription in response to patterning signals, whereas the addition of distal enhancers was needed for full transcriptional output. Synthetic regulatory reconstitution could provide a generalizable strategy for deciphering the regulatory logic of gene expression in complex genomes.",
author = "Sudarshan Pinglay and Milica Bulaji{\'c} and Rahe, {Dylan P.} and Emily Huang and Ran Brosh and Mamrak, {Nicholas E.} and King, {Benjamin R.} and Sergei German and Cadley, {John A.} and Lila Rieber and Nicole Easo and Timoth{\'e}e Lionnet and Shaun Mahony and Maurano, {Matthew T.} and Holt, {Liam J.} and Mazzoni, {Esteban O.} and Boeke, {Jef D.}",
note = "Funding Information: We thank the Mazzoni, Boeke, and Holt labs as well as the Institute for Systems Genetics community for their support, M. Khalfan (Genomics Core Facility at NYU) for making the reform tool publicly available, B. Ragipani for preliminary analysis on motor neuron differentiation markers, N. Zesati and S. Arora for help with preliminary visualization of Hi-C data, the Experimental Pathology core at NYU Langone for help with sectioning, and J. Skok and D. Reinberg for their insights. Supported by NHGRI grant RM1HG009491 (J.B., M.T.M., and E.O.M.), NINDS grant R01NS100897 and NIGMS grant R01GM138876 (E.O.M.), New York State Stem Cell Science predoctoral training grant C322560GG (M.B.), NIH grants R01AG075272 and R01GM127538 and Melanoma Research Foundation Award 687306 (T.L.), and NIH grant F32CA239394 (B.R.K.). Publisher Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved.",
year = "2022",
month = jul,
day = "1",
doi = "10.1126/science.abk2820",
language = "English (US)",
volume = "377",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6601",
}