Suhas S.P. Rao
Stanford University
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Publication
Featured researches published by Suhas S.P. Rao.
Proceedings of the National Academy of Sciences of the United States of America | 2015
Adrian L. Sanborn; Suhas S.P. Rao; Su-Chen Huang; Neva C. Durand; Miriam Huntley; Andrew Jewett; Ivan D. Bochkov; Dharmaraj Chinnappan; Ashok Cutkosky; Jian Li; Kristopher P. Geeting; Andreas Gnirke; Alexandre Melnikov; Doug McKenna; Elena K. Stamenova; Eric S. Lander; Erez Lieberman Aiden
Significance When the human genome folds up inside the cell nucleus, it is spatially partitioned into numerous loops and contact domains. How these structures form is unknown. Here, we show that data from high-resolution spatial proximity maps are consistent with a model in which a complex, including the proteins CCCTC-binding factor (CTCF) and cohesin, mediates the formation of loops by a process of extrusion. Contact domains form as a byproduct of this process. The model accurately predicts how the genome will fold, using only information about the locations at which CTCF is bound. We demonstrate the ability to reengineer loops and domains in a predictable manner by creating highly targeted mutations, some as small as a single base pair, at CTCF sites. We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair.
Cell systems | 2016
Neva C. Durand; Muhammad S. Shamim; Ido Machol; Suhas S.P. Rao; Miriam Huntley; Eric S. Lander; Erez Lieberman Aiden
Hi-C experiments explore the 3D structure of the genome, generating terabases of data to create high-resolution contact maps. Here, we introduce Juicer, an open-source tool for analyzing terabase-scale Hi-C datasets. Juicer allows users without a computational background to transform raw sequence data into normalized contact maps with one click. Juicer produces a hic file containing compressed contact matrices at many resolutions, facilitating visualization and analysis at multiple scales. Structural features, such as loops and domains, are automatically annotated. Juicer is available as open source software at http://aidenlab.org/juicer/.
Cell | 2017
Andres Canela; Yaakov Maman; Seolkyoung Jung; Nancy Wong; Elsa Callen; Amanda Day; Kyong-Rim Kieffer-Kwon; Aleksandra Pekowska; Hongliang Zhang; Suhas S.P. Rao; Su-Chen Huang; Peter J. McKinnon; Peter D. Aplan; Yves Pommier; Erez Lieberman Aiden; Rafael Casellas; André Nussenzweig
In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT.
Molecular Cell | 2017
Kyong Rim Kieffer-Kwon; Keisuke Nimura; Suhas S.P. Rao; Jianliang Xu; Seolkyoung Jung; Aleksandra Pekowska; Marei Dose; Evan Stevens; Ewy Mathe; Peng Dong; Su Chen Huang; Maria Aurelia Ricci; Laura Baranello; Ying Zheng; Francesco Tomassoni Ardori; Wolfgang Resch; Diana A. Stavreva; Steevenson Nelson; Michael J. McAndrew; Adriel Casellas; Elizabeth H. Finn; Charles Gregory; Brian Glenn St Hilaire; Steven M. Johnson; Wendy Dubois; Maria Pia Cosma; Eric Batchelor; David Levens; Robert D. Phair; Tom Misteli
50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.
bioRxiv | 2017
Suhas S.P. Rao; Su-Chen Huang; Brian Glenn St Hilaire; Jesse M. Engreitz; Elizabeth M. Perez; Kyong-Rim Kieffer-Kwon; Adrian L. Sanborn; Sarah E. Johnstone; Ivan D. Bochkov; Xingfan Huang; Muhammad S. Shamim; Arina D. Omer; Bradley E. Bernstein; Rafael Casellas; Eric S. Lander; Erez Lieberman Aiden
The human genome folds to create thousands of intervals, called “contact domains,” that exhibit enhanced contact frequency within themselves. “Loop domains” form because of tethering between two loci - almost always bound by CTCF and cohesin – lying on the same chromosome. “Compartment domains” form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loci in different compartments that had been in the same loop domain become more segregated. Loss of loop domains does not lead to widespread ectopic gene activation, but does affect a significant minority of active genes. In particular, cohesin loss causes superenhancers to co-localize, forming hundreds of links within and across chromosomes, and affecting the regulation of nearby genes. Cohesin restoration quickly reverses these effects, consistent with a model where loop extrusion is rapid.
bioRxiv | 2018
Guy Nir; Irene Farabella; Cynthia Pérez Estrada; Carl G. Ebeling; Brian J. Beliveau; Hiroshi Sasaki; Soun H. Lee; Son C. Nguyen; Ruth B. McCole; Shyamtanu Chattoraj; Jelena Erceg; Jumana AlHaj Abed; Nuno Martins; Huy Nguyen; Mohammed A. Hannan; Sheikh Russell; Neva C. Durand; Suhas S.P. Rao; Jocelyn Y. Kishi; Paula Soler-Vila; Michele Di Pierro; José N. Onuchic; Steven P. Callahan; John M. Schreiner; Jeff Stuckey; Peng Yin; Erez Lieberman Aiden; Marc A. Marti-Renom; C.-ting Wu
Chromosome structure is thought to be crucial for proper functioning of the nucleus. Here, we present a method for visualizing chromosomal DNA at super-resolution and then integrating Hi-C data to produce three-dimensional models of chromosome organization. We begin by applying Oligopaint probes and the single-molecule localization microscopy methods of OligoSTORM and OligoDNA-PAINT to image 8 megabases of human chromosome 19, discovering that chromosomal regions contributing to compartments can form distinct structures. Intriguingly, our data also suggest that homologous maternal and paternal regions may be differentially organized. Finally, we integrate imaging data with Hi-C and restraint-based modeling using a method called integrative modeling of genomic regions (IMGR) to increase the genomic resolution of our traces to 10 kb. One Sentence Summary Super-resolution genome tracing, contact maps, and integrative modeling enable 10 kb resolution glimpses of chromosome folding.
Cell | 2014
Suhas S.P. Rao; Miriam Huntley; Neva C. Durand; Elena K. Stamenova; Ivan D. Bochkov; James Robinson; Adrian L. Sanborn; Ido Machol; Arina D. Omer; Eric S. Lander; Erez Lieberman Aiden
Cell | 2017
Suhas S.P. Rao; Su Chen Huang; Brian Glenn St Hilaire; Jesse M. Engreitz; Elizabeth M. Perez; Kyong Rim Kieffer-Kwon; Adrian L. Sanborn; Sarah E. Johnstone; Gavin Bascom; Ivan D. Bochkov; Xingfan Huang; Muhammad S. Shamim; Jaeweon Shin; Douglass Turner; Ziyi Ye; Arina D. Omer; James Robinson; Tamar Schlick; Bradley E. Bernstein; Rafael Casellas; Eric S. Lander; Erez Lieberman Aiden
Cell | 2018
Laura Vian; Aleksandra Pekowska; Suhas S.P. Rao; Kyong-Rim Kieffer-Kwon; Seolkyoung Jung; Laura Baranello; Su-Chen Huang; Laila El Khattabi; Marei Dose; Nathanael Pruett; Adrian L. Sanborn; Andres Canela; Yaakov Maman; Anna Oksanen; Wolfgang Resch; Xingwang Li; Byoungkoo Lee; Alexander L. Kovalchuk; Zhonghui Tang; Steevenson Nelson; Michele Di Pierro; Ryan R. Cheng; Ido Machol; Brian Glenn St Hilaire; Neva C. Durand; Muhammad S. Shamim; Elena Stamenova; José N. Onuchic; Yijun Ruan; André Nussenzweig
Archive | 2017
Erez Lieberman Aiden; Lander, Eric, S.; Suhas S.P. Rao; Su-Chen Huang; Sanborn, Adrian, L.; Durand, Neva, C.; Miriam Huntley; Andrew Jewett