Thursday, November 21, 2024 11/21/2024

Models and Algorithms for Biological Networks and Polymers: Stochastic Probability Landscape and Chromatin Ensembles

Award Number: R35GM127084
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Program Director/Principal Investigator (Liang, Jie): PROJECT SUMMARY/ABSTRACT We will continue our study of biopolymers and their interactions at two levels. At the molecular network level, we will study the A) probability landscape of stochastic networks of molecular reactions. We will develop efficient computational tools to construct exact probability landscapes in high-dimension, quantify probability discrete fluxes, and characterize their exact topology. These powerful tools will be applied to gain mechanistic understanding of stochastic control of network phenotypes in a number of important biological problems. At the (sub)cellular level, we will study B) biophysics of 3D chromatin folding. We will develop algorithms to identify driver interactiomes that can generate large ensembles of accurate models of single-cell 3D chromatin conformations consistent with Hi-C and single-cell experimental data. Our methods will be applied to study foundational problems of 3D genome to gain understanding of principles of genome organization. In A), we will study stochastic reaction networks of molecules to gain mechanistic understanding of their behavior. Many important cellular processes involve a small copy number of molecules of transcription factors, enzymes, and signaling molecules. Stochasticity and rare events arising from such low copy number reactions are important for processes such as embryonic development, stem cell differentiation, and nongenetic heterogeneity. Our approach will be based on the fundamental framework of the stochastic kinetic processes and the discrete chemical master equation (dCME). The central tasks are: 1) constructing the probability landscape of the network, and from which to 2) gain analytical insight into mechanism of network behavior. For 1), we have developed the ACME method that can construct the exact probability landscapes of a large class of complex stochastic reaction networks and will make further improvement. For 2), we will develop landscape analysis tools using persistent homology that can compute the exact topology of the high-dimensional probability landscape. We have also developed the concept of discrete fluxes and methods for its computation. We will further formulate and generalize the concept of discrete rotational flux to higher dimension. These developments will enable global and mechanistic understanding of the behavior of stochastic networks through accurately constructed probability landscape and exactly computed topological structures. Our work will open up new frontiers for investigations, many of which are currently not computationally feasible. Specifically, we will construct probability landscapes of networks, study how global flux maps evolve and how phenotype switching occur. We will generalize the discovery of stochastic oscillation and investigate higher-order oscillatory behavior of networks, where probability mass may be transferred through higher-dimensional k-channels. In addition, we will carry-out in-depth analysis on a selected set of important biological problems, including stochastic control of mRNA splicing/transcription at single-cell level, initiation of protein fibril aggregation, network architectures for multi-stability and maintenance of epigenetic states, and switching of cellular phenotypes. In B), we will study the biophysical principles of 3D genome organization. We will develop computational tools to generate thoroughly sampled large ensembles of coarse-grained polymer models of 3D chromatin structures based on experimental Hi-C and other data. We will develop strategies to study a number of fundamental problems: We will determine and uncover the minimal sets of critical driver interactions sufficient to determine folding of chromatin at specific loci and at whole chromosome level. We will further investigate how chromatin-nuclear envelope interactions, along with chromatin driver interactome, nuclear bodies, and speckles, orchestrate the overall 3D genome organization. We will decipher the persistent driver interactomes at different genomic loci, which are preserved across different tissues and are responsible for the formation of common genomic structural scaffolds and folding landscapes. We will also identify adaptive interactomes that differ among tissues and inferring how they evolve and rewire during development. We will further infer how these temporally evolving structural interactomes spatially arrange genomic elements and how they may influence structural gene accessibility at genome scale. 0925-0001 (Rev. 03/16) Page Continuation Format Page


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	6	11/14/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $779,969 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	002	6	8/21/2024	SUPPLEMENT FOR EXPANSION	$250,000
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	001	6	12/26/2023	COMPETING CONTINUATION	$529,969
2024	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	5	12/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $779,969

Issue Date FY: 2022 ( Subtotal = $465,489 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	5	4/22/2022	NON-COMPETING CONTINUATION	$465,489
														Subtotal = $465,489

Issue Date FY: 2021 ( Subtotal = $512,489 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	4	4/21/2021	NON-COMPETING CONTINUATION	$512,489
														Subtotal = $512,489

Issue Date FY: 2020 ( Subtotal = $465,489 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	3	4/15/2020	NON-COMPETING CONTINUATION	$465,489
														Subtotal = $465,489

Issue Date FY: 2019 ( Subtotal = $465,489 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	2	4/29/2019	NON-COMPETING CONTINUATION	$465,489
														Subtotal = $465,489

Issue Date FY: 2018 ( Subtotal = $512,489 )
2018	2018	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	5/8/2018	NEW	$512,489
														Subtotal = $512,489

Grand Total All Awards = $3,201,414

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Models and Algorithms for Biological Networks and Polymers: Stochastic Probability Landscape and Chromatin Ensembles

Award Number: R35GM127084

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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