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Student Faculty Collaborate
Data Science Institute

Zimmermann Laboratory

Location
HRC5 - Mellowes Center

Zimmermann lab joining with Dr.s Urrutia, Lomberk, and team, for ASHG 2025

Interests

  • Human genetic diseases of the epigenome
  • Mechanistic interpretation of inter-individual genetic variation using protein structural models
  • Rare disease discovery and diagnosis via enhanced computational approaches
  • Scaling our approaches developed for heritable genetic diseases, to populations and their many one-of-a-kind variations
  • Integrative modeling to bridge across multiple experiments and derive highly dynamic models of protein complex鈥檚 function
  • Multi-omics data as functional readouts of chromatin regulating enzymes
  • Identifying and characterizing molecular mechanisms that underly genetic variations
  • Defining genetic diseases through team science and integrative modeling efforts to link genotype to mechanism, and to patient manifestations
  • Modeling inter-individual genetic effects on the regulation of epigenetic regulatory enzymes across health and disease


Computational Structural Genomics

Computational Structural Genomics: A Transformational Approach for Biology and Medicine

Deep Variant Phenotyping (DVP) resolves variants by their underlying mechanism. In this generalized diagram, we depict the CIMG process. Investigators nominate cohorts to VEB, primarily VUS and a few pathogenic variants. We identify functional context to guide molecular modeling. In a recent example, our team evaluated the two functional states of the JAK3 homodimer by structure and dynamics. Our output includes a report where we mechanistically interpret the cohort, facilitating computer-enhanced hypothesis-driven research among the clinical and investigative collaborators.

ABCC6 molecular mechansims diagram

Quantifying Disparate Molecular Mechanisms Underlying the Effects of Numerous Variants of Uncertain Significance

We applied DVP to ABCC6 and resolved molecular mechanisms for 379 missense variants, 90% of which are clinical VUS. ABCC6 only has 45 鈮� 1* pathogenic variants. Thus, the transformative nature of DVP is apparent. Importantly, concepts like structural stability, individually, only resolve a subset of variants, showing how a comprehensive and integrative approach is needed. A) Domain organization of ABCC6. B) 3D hotspots that we identified. C) Six discrete mechanisms outlined.

MT supercomples pilot

Scaling Genomic Data Interpretation to Complexes, Super-Complexes, and Beyond

The MT super-complex reveals that VUS are distributed throughout its quaternary structure. A) We mark the location if each selected variant with a red sphere. B) MT-ND4:E222 and C) MT-ND5:E145 are within internal pockets lined with positive and negative charges, likely facilitating the flexible conformational changes that are required for electron transport. D) Selected mutations are nearby in space and typically at the ends of alpha helices where they also likely modulate flexibility. E) Structure-based stability calculations reveal the disruption to the complex.

Fold types variation

Quantifying the Domain-Type-Level Flexibilities that Need to be Accounted for Computational Structural Genomics

: We studied the entire human proteome as predicted by AlphaFold2 and quantified agreement between experiment and prediction, where possible. Across 628 CATH topologies that have at least 10 experimental structures we observed a spectrum of flexibility.

Piloting protein surface scores

Piloting protein surface-based scores for interpreting the effects of genetic variants at distant functional sites

. A,C) Crystal structures of Granzyme H and IGF1R show local charge distribution for point mutations, circled in orange. B,D) The distribution of electrostatic potential differs between wild type and variant surfaces.

 

Mechanisms of the BAF Chromatin Remodeling Complex

The BAF complex, named Brahma Associated Factor for its necessary role in cellular transcription, is a critical regulator of the genome. Genetic changes to the many genes that collectively encode BAF function cause a spectrum of rare diseases of the epigenome and frequently contribute to cancer. Our team is integrative and AI-empowered approaches to model the dynamic features of this complex in detail and in multiple states. In this way, we are bringing to light more context-aware and sensitive genomics. Additionally, we are pioneering ways to address the extensive unresolved and intrinsically disordered sections. This flythrough animation highlights the active site of the SMARCA4 ATPase, then zooms out to one model of the complex, and shows a representation of the long unresolved regions.

 

RAG Complex Modeling for Rare Diseases

The RAG complex is required for our immune system to adapt to pathogens. We work with the nation’s experts for Inborn Errors of Immunity, where children are born without a normally formed immune system. Our team models the protein complex in multiple steps of its functional cycle. In this way, we go beyond structural bioinformatics to better bridge the structure-function relationship to cell biology and the context-specific and mechanistic information that the field needs for next-generation genomics interpretation. Our approach increases diagnostic rates, points to testable hypotheses, and paves paths towards therapeutics.

Our Current Members

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Michael T. Zimmermann, PhD

Director, Computational Structural Genomics Unit and Associate Director, Computational Biology, Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine; Associate Professor, Data Science Institute

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Xiaowei Dong

Research Technologist I, Data Science Institute - Division of Biostatistics

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Jane Gresser, MS

Bioinformatics Analyst I, Data Science Institute - Division of Biostatistics

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Neshatul Haque, PhD

Postdoctoral Researcher

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Jessica Wagenknecht, PhD

Bioinformatics Analyst II, Data Science Institute - Division of Biostatistics

Image Gallery

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Mellowes Center timeline 2025

Mellowes Center timeline 2025

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MTZ at KLF Society 2024 Greece

MTZ at KLF Society 2024 Greece

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MTZ at UDNI 2025 Brasil

MTZ at UDNI 2025 Brasil

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Zimm lab at ASHG 2023

Zimm lab at ASHG 2023

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Zimm lab at ASHG 2024

Zimm lab at ASHG 2024

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Recent Publications

  • (Keehan LA, Ono-Minagi H, Hadhud M, Rips J, Hinds DM, Fischer AJ, Bartlett JA, McCray PB, Qawasmi N, Nathan N, Louvrier C, Desroziers T, Damme M, Griese M, Wegner DJ, Cole FS, Wambach JA, Wheeler MT, Burbelo PD, Bonner DE, Undiagnosed Diseases Network, Bernstein JA, Chiorini JA, Breuer O, Milla C.) Genet Med. 2026 Apr;28(4):102531 PMID: 41653023 PMCID: PMC13078123 SCOPUS ID: 2-s2.0-105032104322 02/07/2026

  • (Pollin G, Mathison AJ, Leverence EN, De Assuncao TM, Iovanna J, Hong JC, Zimmermann MT, Urrutia R, Lomberk G.) Epigenomes. 2026 Mar 10;10(1) PMID: 41892368 PMCID: PMC13025234 SCOPUS ID: 2-s2.0-105034413893 03/27/2026

  • (Dzikowski M, Pollin G, Gunia V, Butler S, Enkhtuul B, Gavina Chavez J, Zimmermann MT, Mathison A, Urrutia R, Lomberk G.) Front Cell Dev Biol. 2026;14:1748541 PMID: 41890907 PMCID: PMC13013501 SCOPUS ID: 2-s2.0-105033634422 03/27/2026

  • (Wagenknecht JB, Haque N, Jorge SD, Ratnasinghe BD, Urrutia R, Gahl WA, Ziegler SG, Zimmermann MT.) International Journal of Molecular Sciences. February 2026;27(4) SCOPUS ID: 2-s2.0-105031531543 02/01/2026

  • (Stewart R, Ezell KM, Bell DS, Corner B, McMinn A, Cogan JD, Hamid R, Rives L, Phillips JA 3rd, Paddu N, Srivastava G, Marom R, Ladha FA, Soler-Alfonso C, Franciskovich R, Koziura M, Pruthi S, Richard G, Sheedy CB, Undiagnosed Diseases Network, Cassini T.) Am J Med Genet A. 2026 Jan;200(1):205-214 PMID: 40838347 SCOPUS ID: 2-s2.0-105013894374 08/21/2025

  • (Furuta Y, Ezell KM, Hamid R, Cogan JD, Cassini TA, Rives L, McMinn A, Shah S, Peltier AC, Layfield S, Fletcher RS, Tedder ML, Louie RJ, Lee JA, Kerkhof J, Rzasa J, Sadikovic B, Al Mamun A, Sheehan JH, Moth CW, Meiler J, Vawter-Lee M, Mendoza-Sengco PM, Holzen JB, Pruthi S, Phillips JA 3rd, Tinker RJ, Undiagnosed Diseases Network.) Mol Genet Genomic Med. 2025 Dec;13(12):e70165 PMID: 41407309 PMCID: PMC12711360 SCOPUS ID: 2-s2.0-105025171807 12/18/2025

  • (Veluri R, Pollin G, Wagenknecht JB, Urrutia R, Zimmermann MT.) NAR Genom Bioinform. 2025 Dec;7(4):lqaf178 PMID: 41347230 PMCID: PMC12673850 12/05/2025

  • (Pinto E Vairo F, Zimmermann MT, Wagenknecht J, Jorge SD, Tian S, Vierkant RA, Luehrs AC, Milech de Assunção T, Mathison A, Atwal PS, Cao Y, Allen AM, Klee EW, Urrutia R, Lazaridis KN.) Hepatology. 2025 Dec 01;82(6):1512-1522 PMID: 39879586 SCOPUS ID: 2-s2.0-85217105777 01/29/2025

  • (Cooperstein IB, Marwaha S, Ward A, Kobren SN, Carter JN, Undiagnosed Diseases Network, Wheeler MT, Marth GT.) Genome Med. 2025 Oct 21;17(1):127 PMID: 41121346 PMCID: PMC12539062 SCOPUS ID: 2-s2.0-105019725183 10/22/2025

  • (Dong X, Haque N, Wagenknecht JB, Zimmermann MT.) Endocr Connect. 2025 Oct 01;14(10) PMID: 41175859 PMCID: PMC12579490 11/02/2025

  • (Kobren SN, Moldovan MA, Reimers R, Traviglia D, Li X, Barnum D, Veit A, Corona RI, Carvalho Neto GV, Willett J, Berselli M, Ronchetti W, Nelson SF, Martinez-Agosto JA, Sherwood R, Krier J, Kohane IS, Undiagnosed Diseases Network, Sunyaev SR.) Nat Commun. 2025 Aug 07;16(1):7267 PMID: 40770127 PMCID: PMC12328722 SCOPUS ID: 2-s2.0-105013076026 08/07/2025

  • (Fazal S, Dashnow H, Dohrn MF, Raposo J, Hiatt L, Danzi MC, Xu IRL, Toro C, Adams DR, Usdin K, Hayward B, Kobren SN, Sunyaev SR, Spillmann RC, Shashi V, Rebelo A, Bademci G, Undiagnosed Diseases Network, Tekin M, Quinlan AR, Zuchner S.) Genet Med. 2025 Aug;27(8):101462 PMID: 40417743 PMCID: PMC12318663 SCOPUS ID: 2-s2.0-105009588600 05/26/2025

  • (Dong X, Haque N, Wagenknecht JB, Zimmermann MT.) bioRxiv. 2025 Jul 10 PMID: 40672303 PMCID: PMC12265623 07/17/2025

  • (Wagenknecht JB, Haque N, Jorge SD, Ratnasinghe BD, Urrutia R, Gahl WA, Ziegler SG, Zimmermann MT.) bioRxiv. 2025 Jun 23 PMID: 40667354 PMCID: PMC12262381 07/16/2025

  • (Veluri R, Pollin G, Wagenknecht JB, Urrutia R, Zimmermann MT.) bioRxiv. 2025 Feb 05 PMID: 39974886 PMCID: PMC11838408 02/20/2025

  • (Thouvenel CD, Tipton CM, Yamazaki Y, Zhang TT, Rylaarsdam S, Hom JR, Snead C, Zhu C, Li QZ, Lee YN, Kawai T, Haque N, Zimmermann MT, Ponnan SM, Jackson SW, James RG, Sanz I, Notarangelo LD, Torgerson TR, Ochs HD, Rawlings DJ, Allenspach EJ.) J Clin Immunol. 2025 Jan 15;45(1):66 PMID: 39812873 PMCID: PMC11735530 SCOPUS ID: 2-s2.0-85217272111 01/15/2025

  • (Veluri R, Pollin G, Wagenknecht JB, Urrutia R, Zimmermann MT.) Nar Genomics and Bioinformatics. 1 December 2025;7(4) SCOPUS ID: 2-s2.0-105023888502 12/01/2025

  • (Dong X, Haque N, Wagenknecht JB, Zimmermann MT.) Endocrine Connections. October 2025;14(10) SCOPUS ID: 2-s2.0-105021958230 10/01/2025

  • (Dong J, Zimmermann MT, Haque N, Arsang-Jang S, Saber W, Gai X, Urrutia R.) Transplantation Reports. February 2025;10(1) SCOPUS ID: 2-s2.0-85215105221 02/01/2025

  • (DeVoe E, Reddi HV, Taylor BW, Stachowiak S, Geurts JL, George B, Shaker R, Urrutia R, Zimmermann MT.) J Comput Biol. 2025 Jan;32(1):89-103 PMID: 39659251 PMCID: PMC11839515 SCOPUS ID: 2-s2.0-85215145104 12/11/2024

  • (Pollin G, Chi YI, Mathison AJ, Zimmermann MT, Lomberk G, Urrutia R.) Epigenomics. 2025 Jan;17(1):5-20 PMID: 39632680 PMCID: PMC11703355 SCOPUS ID: 2-s2.0-85210974733 12/05/2024

  • (Dsouza NR, Haque N, Tripathi S, Zimmermann MT.) Int J Mol Sci. 2024 Nov 08;25(22) PMID: 39596086 PMCID: PMC11594063 SCOPUS ID: 2-s2.0-85210224251 11/27/2024

  • (Gong M, Li J, Qin Z, Machado Bressan Wilke MV, Liu Y, Li Q, Liu H, Liang C, Morales-Rosado JA, Cohen ASA, Hughes SS, Sullivan BR, Waddell V, van den Boogaard MH, van Jaarsveld RH, van Binsbergen E, van Gassen KL, Wang T, Hiatt SM, Amaral MD, Kelley WV, Zhao J, Feng W, Ren C, Yu Y, Boczek NJ, Ferber MJ, Lahner C, Elliott S, Ruan Y, Mignot C, Keren B, Xie H, Wang X, Popp B, Zweier C, Piard J, Coubes C, Mau-Them FT, Safraou H, Innes AM, Gauthier J, Michaud JL, Koboldt DC, Sylvie O, Willems M, Tan WH, Cogne B, Rieubland C, Braun D, McLean SD, Platzer K, Zacher P, Oppermann H, Evenepoel L, Blanc P, El Khattabi L, Haque N, Dsouza NR, Zimmermann MT, Urrutia R, Klee EW, Shen Y, Du H, Rappaport L, Liu CM, Chen X.) Am J Hum Genet. 2024 Nov 07;111(11):2392-2410 PMID: 39419027 PMCID: PMC11568763 SCOPUS ID: 2-s2.0-85207372821 10/18/2024

  • (Haque N, Wagenknecht JB, Ratnasinghe BD, Zimmermann MT.) PLoS One. 2024;19(11):e0313308 PMID: 39591473 PMCID: PMC11594405 SCOPUS ID: 2-s2.0-85210375728 11/26/2024

  • (Dsouza NR, Haque N, Tripathi S, Zimmermann MT.) International Journal of Molecular Sciences. November 2024;25(22) SCOPUS ID: 2-s2.0-85210224251 11/01/2024

Publications of from the

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