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Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

ABSTRACT: Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

SUBMITTER: Bryant L

PROVIDER: S-EPMC7821880 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Bryant Laura L Li Dong D Cox Samuel G SG Marchione Dylan D Joiner Evan F EF Wilson Khadija K Janssen Kevin K Lee Pearl P March Michael E ME Nair Divya D Sherr Elliott E Fregeau Brieana B Wierenga Klaas J KJ Wadley Alexandrea A Mancini Grazia M S GMS Powell-Hamilton Nina N van de Kamp Jiddeke J Grebe Theresa T Dean John J Ross Alison A Crawford Heather P HP Powis Zoe Z Cho Megan T MT Willing Marcia C MC Manwaring Linda L Schot Rachel R Nava Caroline C Afenjar Alexandra A Lessel Davor D Wagner Matias M Klopstock Thomas T Winkelmann Juliane J Catarino Claudia B CB Retterer Kyle K Schuette Jane L JL Innis Jeffrey W JW Pizzino Amy A Lüttgen Sabine S Denecke Jonas J Strom Tim M TM Monaghan Kristin G KG Yuan Zuo-Fei ZF Dubbs Holly H Bend Renee R Lee Jennifer A JA Lyons Michael J MJ Hoefele Julia J Günthner Roman R Reutter Heiko H Keren Boris B Radtke Kelly K Sherbini Omar O Mrokse Cameron C Helbig Katherine L KL Odent Sylvie S Cogne Benjamin B Mercier Sandra S Bezieau Stephane S Besnard Thomas T Kury Sebastien S Redon Richard R Reinson Karit K Wojcik Monica H MH Õunap Katrin K Ilves Pilvi P Innes A Micheil AM Kernohan Kristin D KD Costain Gregory G Meyn M Stephen MS Chitayat David D Zackai Elaine E Lehman Anna A Kitson Hilary H Martin Martin G MG Martinez-Agosto Julian A JA Nelson Stan F SF Palmer Christina G S CGS Papp Jeanette C JC Parker Neil H NH Sinsheimer Janet S JS Vilain Eric E Wan Jijun J Yoon Amanda J AJ Zheng Allison A Brimble Elise E Ferrero Giovanni Battista GB Radio Francesca Clementina FC Carli Diana D Barresi Sabina S Brusco Alfredo A Tartaglia Marco M Thomas Jennifer Muncy JM Umana Luis L Weiss Marjan M MM Gotway Garrett G Stuurman K E KE Thompson Michelle L ML McWalter Kirsty K Stumpel Constance T R M CTRM Stevens Servi J C SJC Stegmann Alexander P A APA Tveten Kristian K Vøllo Arve A Prescott Trine T Fagerberg Christina C Laulund Lone Walentin LW Larsen Martin J MJ Byler Melissa M Lebel Robert Roger RR Hurst Anna C AC Dean Joy J Schrier Vergano Samantha A SA Norman Jennifer J Mercimek-Andrews Saadet S Neira Juanita J Van Allen Margot I MI Longo Nicola N Sellars Elizabeth E Louie Raymond J RJ Cathey Sara S SS Brokamp Elly E Heron Delphine D Snyder Molly M Vanderver Adeline A Simon Celeste C de la Cruz Xavier X Padilla Natália N Crump J Gage JG Chung Wendy W Garcia Benjamin B Hakonarson Hakon H HH Bhoj Elizabeth J EJ

Science advances 20201202 49

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone p ...[more]

PMID: 33268356

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Project description:Chromatin dynamics can regulate all DNA-dependent processes. Access to DNA within chromatin is orchestrated mainly by histones and their posttranslational modifications (PTMs). Like other eukaryotes, the apicomplexan parasite Toxoplasma gondii encodes four canonical histones and five histone variants. In contrast, the linker histone (H1) has never been identified in apicomplexan parasites. In other eukaryotes, histone H1 compacts the chromatin by linking the nucleosome and increasing the DNA compaction. H1 is a multifunctional protein and can be involved in different steps of DNA metabolism or associated with protein complexes related to distinct biological processes. We have identified a novel protein in T. gondii ("TgH1-like") that, although lacking the globular domain of mammalian H1, is remarkably like the H1-like proteins of bacteria and trypanosomatids. Our results demonstrate that TgH1-like is a nuclear protein associated with chromatin and other histones. Curiously, TgH1-like is also in the nucleolus and associated with ribosomal proteins, indicating a versatile function in this parasite. Although knockout of the tgh1-like gene does not affect the cell cycle, it causes endopolygeny and asynchronous division. Interestingly, mutation of posttranslationally modified amino acids results in defects in cell division like those in the Δtgh1-like mutant, showing that these sites are important for protein function. Furthermore, in the bradyzoite stage, this protein is expressed only in dividing parasites, reinforcing its importance in cell division. Indeed, the absence of TgH1-like decreases compaction of peripheral chromatin, confirming its role in the chromatin modulation in T. gondii. IMPORTANCE Histone H1, or linker histone, is an important protein that binds to the nucleosome, aiding chromatin compaction. Here, we characterize for the first time a linker histone in T. gondii, named TgH1-like. It is a small and basic protein that corresponds only to the C-terminal portion of the human H1 but is similar to histone H1 from trypanosomatids and bacteria. TgH1-like is located in the nucleus, interacts with nucleosome histones, and acts in chromatin structure and cell division. Our findings show for the first time the presence of a histone H1 protein in an apicomplexan parasite and will provide new insights into cell division and chromatin dynamics in T. gondii and related parasites.

Dataset Information

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Publications

Histone H3.3 beyond cancer: Germline mutations in <i>Histone 3 Family 3A and 3B</i> cause a previously unidentified neurodegenerative disorder in 46 patients.

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