Building, benchmarking, and exploring perturbative maps of transcriptional and morphological data DOI Creative Commons
Safiye Çelik, Jan-Christian Hütter,

Sandra Melo Carlos

et al.

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(10), P. e1012463 - e1012463

Published: Oct. 1, 2024

The continued scaling of genetic perturbation technologies combined with high-dimensional assays such as cellular microscopy and RNA-sequencing has enabled genome-scale reverse-genetics experiments that go beyond single-endpoint measurements growth or lethality. Datasets emerging from these can be to construct perturbative “maps biology”, in which readouts various manipulations (e.g., CRISPR-Cas9 knockout, CRISPRi knockdown, compound treatment) are placed unified, relatable embedding spaces allowing for the generation sets pairwise comparisons. These maps biology capture known biological relationships uncover new associations used downstream discovery tasks. Construction involves many technical choices both experimental computational protocols, motivating design benchmark procedures evaluate map quality a systematic, unbiased manner. Here, we (1) establish standardized terminology steps involved building, (2) introduce key classes benchmarks assess maps, (3) 18 four datasets employing different cell types, technologies, data readout modalities, (4) generate metrics constructed investigate reasons performance variations, (5) demonstrate utility discover by suggesting roles two largely uncharacterized genes.

Language: Английский

Functional partitioning of transcriptional regulators by patterned charge blocks DOI Creative Commons
Heankel Lyons,

Reshma T Veettil,

Prashant Pradhan

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 327 - 345.e28

Published: Jan. 1, 2023

Language: Английский

Citations

189
Deciphering the multi-scale, quantitative cis-regulatory code DOI Creative Commons
Seungsoo Kim, Joanna Wysocka

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(3), P. 373 - 392

Published: Jan. 23, 2023

Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome cellular state remains central goal of biology. Here, we discuss major layers regulation influence transcriptional outputs are encoded by DNA sequence context. We first transcription factors bind specific sequences dosage-dependent cooperative manner then proceed to cofactors facilitate factor function mediate activity modular elements such as enhancers, silencers, promoters. consider complex poorly understood interplay these diverse within regulatory landscapes its relationships with chromatin states nuclear organization. propose mechanistically informed, quantitative model integrates multiple will be key ultimately cracking code.

Language: Английский

Citations

166
Transcription factors interact with RNA to regulate genes DOI
Ozgur Oksuz, Jonathan E. Henninger, Robert Warneford-Thomson

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(14), P. 2449 - 2463.e13

Published: July 1, 2023

Language: Английский

Citations

156
Enhancer–promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness DOI
Shreeta Chakraborty,

Nina Kopitchinski,

Zhenyu Zuo

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 280 - 290

Published: Jan. 30, 2023

Language: Английский

Citations

74
The Mediator complex regulates enhancer-promoter interactions DOI Creative Commons

Shyam Ramasamy,

Abrar Aljahani, Magdalena A. Karpińska

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(7), P. 991 - 1000

Published: July 1, 2023

Abstract Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target promoters. However, the molecular mechanisms by which interactions promoters are formed not well understood. Here, we investigate function of Mediator complex in regulation enhancer-promoter interactions, combining rapid protein depletion high-resolution MNase-based chromosome conformation capture approaches. We show that leads to reduced interaction frequencies, associated with a strong decrease expression. In addition, find increased CTCF-binding sites upon depletion. These changes chromatin architecture redistribution Cohesin on reduction occupancy at enhancers. Together, our results indicate complexes contribute provide insights into communication is regulated.

Language: Английский

Citations

55
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation DOI
Jin Yang, Anders S. Hansen

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 574 - 591

Published: Feb. 27, 2024

Language: Английский

Citations

51
Regulation of the RNA polymerase II pre-initiation complex by its associated coactivators DOI
Sohail Malik, Robert G. Roeder

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(11), P. 767 - 782

Published: Aug. 2, 2023

Language: Английский

Citations

47
COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins DOI Creative Commons
Alexander Jussupow,

Divya Bartley,

Lisa J. Lapidus

et al.

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, enable more realistic modeling involving domains without additional costs. COCOMO2 was parametrized directly solubility data improve performance predicting concentration-dependent broader range biomolecular systems compared original version. enables new applications study condensates involve IDPs together assembly also provides expanded foundation development multiscale approaches span residue-level atomistic resolution.

Language: Английский

Citations

3
Genomic regulation of transcription and RNA processing by the multitasking Integrator complex DOI
Sarah A. Welsh, Alessandro Gardini

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 204 - 220

Published: Sept. 30, 2022

Language: Английский

Citations

58
The role of loop extrusion in enhancer-mediated gene activation DOI Creative Commons
Magdalena A. Karpińska,

Aukje Marieke Oudelaar

Current Opinion in Genetics & Development, Journal Year: 2023, Volume and Issue: 79, P. 102022 - 102022

Published: Feb. 25, 2023

Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters three-dimensional (3D) chromatin structures. Despite advances our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers controlled this 3D context. In review, we give an overview recent evidence shows a process loop extrusion plays important role regulation enhancer-promoter communication discuss insights molecular mechanism contributes to enhancer-mediated activation.

Language: Английский

Citations

32