MSTPublications: December 2021
MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
Rachel E. Brown, Justin Jacobse, Shruti A. Anant, Koral M. Blunt, Bob Chen, Paige N. Vega, Chase T. Jones, Jennifer M. Pilat, Frank Revetta, Aidan H. Gorby, Kristy R. Stengel, Yash A. Choksi, Kimmo Palin, M. Blanca Piazuelo, M. Kay Washington, Ken S. Lau, Jeremy A. Goettel, Scott W. Hiebert, Sarah P. Short, Christopher S. Williams
bioRxiv 2021.11.03.467178; doi: https://doi.org/10.1101/2021.11.03.467178
Aberrant epithelial differentiation and regeneration contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium (DSS)-induced colitis. Transcriptomic analyses implicated increased E box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared to unaffected controls. Finally, uncoupling MTG16:E protein interactions only partially phenocopied the enhanced tumorigenicity of Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
Bisphosphate nucleotidase 2 (BPNT2), a molecular target of lithium, regulates chondroitin sulfation patterns in the cerebral cortex and hippocampus.
Eisele BS, Wu AJ, Luka Z, Hale AT, York JD.
Adv Biol Regul. 2021 Dec 9:100858. doi: 10.1016/j.jbior.2021.100858. Online ahead of print.
Bisphosphate nucleotidase 2 (BPNT2) is a member of a family of phosphatases that are directly inhibited by lithium, the first-line medication for bipolar disorder. BPNT2 is localized to the Golgi, where it metabolizes the by-products of glycosaminoglycan sulfation reactions. BPNT2-knockout mice exhibit impairments in total-body chondroitin-4-sulfation which lead to abnormal skeletal development (chondrodysplasia). These mice die in the perinatal period, which has previously prevented the investigation of BPNT2 in the adult nervous system. Previous work has demonstrated the importance of chondroitin sulfation in the brain, as chondroitin-4-sulfate is a major component of perineuronal nets (PNNs), a specialized neuronal extracellular matrix which mediates synaptic plasticity and regulates certain behaviors. We hypothesized that the loss of BPNT2 in the nervous system would decrease chondroitin-4-sulfation and PNNs in the brain, which would coincide with behavioral abnormalities. We used Cre-lox breeding to knockout Bpnt2 specifically in the nervous system using Bpnt2 floxed (fl/fl) animals and a Nestin-driven Cre recombinase. These mice are viable into adulthood, and do not display gross physical abnormalities. We identified decreases in total glycosaminoglycan sulfation across selected brain regions, and specifically show decreases in chondroitin-4-sulfation which correspond with increases in chondroitin-6-sulfation. Interestingly, these changes were not correlated with gross alterations in PNNs. We also subjected these mice to a selection of neurobehavioral assessments and did not identify significant behavioral abnormalities. In summary, this work demonstrates that BPNT2, a known target of lithium, is important for glycosaminoglycan sulfation in the brain, suggesting that lithium-mediated inhibition of BPNT2 in the nervous system warrants further investigation.
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.
Mullins N, Kang J, Campos AI, Coleman JRI, Edwards AC, Galfalvy H, Levey DF, Lori A, Shabalin A, Starnawska A, Su MH, Watson HJ, Adams M, Awasthi S, Gandal M, Hafferty JD, Hishimoto A, Kim M, Okazaki S, Otsuka I, Ripke S, Ware EB, Bergen AW, Berrettini WH, Bohus M, Brandt H, Chang X, Chen WJ, Chen HC, Crawford S, Crow S, DiBlasi E, Duriez P, Fernández-Aranda F, Fichter MM, Gallinger S, Glatt SJ, Gorwood P, Guo Y, Hakonarson H, Halmi KA, Hwu HG, Jain S, Jamain S, Jiménez-Murcia S, Johnson C, Kaplan AS, Kaye WH, Keel PK, Kennedy JL, Klump KL, Li D, Liao SC, Lieb K, Lilenfeld L, Liu CM, Magistretti PJ, Marshall CR, Mitchell JE, Monson ET, Myers RM, Pinto D, Powers A, Ramoz N, Roepke S, Rozanov V, Scherer SW, Schmahl C, Sokolowski M, Strober M, Thornton LM, Treasure J, Tsuang MT, Witt SH, Woodside DB, Yilmaz Z, Zillich L, Adolfsson R, Agartz I, Air TM, Alda M, Alfredsson L, Andreassen OA, Anjorin A, Appadurai V, Soler Artigas M, Van der Auwera S, Azevedo MH, Bass N, Bau CHD, Baune BT, Bellivier F, Berger K, Biernacka JM, Bigdeli TB, Binder EB, Boehnke M, Boks MP, Bosch R, Braff DL, Bryant R, Budde M, Byrne EM, Cahn W, Casas M, Castelao E, Cervilla JA, Chaumette B, Cichon S, Corvin A, Craddock N, Craig D, Degenhardt F, Djurovic S, Edenberg HJ, Fanous AH, Foo JC, Forstner AJ, Frye M, Fullerton JM, Gatt JM, Gejman PV, Giegling I, Grabe HJ, Green MJ, Grevet EH, Grigoroiu-Serbanescu M, Gutierrez B, Guzman-Parra J, Hamilton SP, Hamshere ML, Hartmann A, Hauser J, Heilmann-Heimbach S, Hoffmann P, Ising M, Jones I, Jones LA, Jonsson L, Kahn RS, Kelsoe JR, Kendler KS, Kloiber S, Koenen KC, Kogevinas M, Konte B, Krebs MO, Landén M, Lawrence J, Leboyer M, Lee PH, Levinson DF, Liao C, Lissowska J, Lucae S, Mayoral F, McElroy SL, McGrath P, McGuffin P, McQuillin A, Medland SE, Mehta D, Melle I, Milaneschi Y, Mitchell PB, Molina E, Morken G, Mortensen PB, Müller-Myhsok B, Nievergelt C, Nimgaonkar V, Nöthen MM, O’Donovan MC, Ophoff RA, Owen MJ, Pato C, Pato MT, Penninx BWJH, Pimm J, Pistis G, Potash JB, Power RA, Preisig M, Quested D, Ramos-Quiroga JA, Reif A, Ribasés M, Richarte V, Rietschel M, Rivera M, Roberts A, Roberts G, Rouleau GA, Rovaris DL, Rujescu D, Sánchez-Mora C, Sanders AR, Schofield PR, Schulze TG, Scott LJ, Serretti A, Shi J, Shyn SI, Sirignano L, Sklar P, Smeland OB, Smoller JW, Sonuga-Barke EJS, Spalletta G, Strauss JS, Świątkowska B, Trzaskowski M, Turecki G, Vilar-Ribó L, Vincent JB, Völzke H, Walters JTR, Shannon Weickert C, Weickert TW, Weissman MM, Williams LM, Wray NR, Zai CC, Ashley-Koch AE, Beckham JC, Hauser ER, Hauser MA, Kimbrel NA, Lindquist JH, McMahon B, Oslin DW, Qin X; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Eating Disorders Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; MVP Suicide Exemplar Workgroup; VA Million Veteran Program, Agerbo E, Børglum AD, Breen G, Erlangsen A, Esko T, Gelernter J, Hougaard DM, Kessler RC, Kranzler HR, Li QS, Martin NG, McIntosh AM, Mors O, Nordentoft M, Olsen CM, Porteous D, Ursano RJ, Wasserman D, Werge T, Whiteman DC, Bulik CM, Coon H, Demontis D, Docherty AR, Kuo PH, Lewis CM, Mann JJ, Rentería ME, Smith DJ, Stahl EA, Stein MB, Streit F, Willour V, Ruderfer DM.
Biol Psychiatry. 2021 Sep 9:S0006-3223(21)01570-5. doi: 10.1016/j.biopsych.2021.05.029. Online ahead of print.
PMID: 34861974
Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.
Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.
Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.
Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
This publication was featured in the VUMC reporter!
Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase.
Reisman BJ, Guo H, Ramsey HE, Wright MT, Reinfeld BI, Ferrell PB, Sulikowski GA, Rathmell WK, Savona MR, Plate L, Rubinstein JL, Bachmann BO.
Nat Chem Biol. 2021 Dec 2. doi: 10.1038/s41589-021-00900-9. Online ahead of print.
Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.
Beyond the Scalpel: Attracting and Nurturing Surgeon-Scientists in Plastic Surgery.
Baker NF, Colazo JM, Gosain AK.
Plast Reconstr Surg. 2021 Dec 13. doi: 10.1097/PRS.0000000000008786. Online ahead of print.
Learning through a Pandemic: The Current State of Knowledge on COVID-19 and Cancer.
Elkrief A, Wu JT, Jani C, Enriquez KT, Glover M, Shah MR, Shaikh HG, Beeghly-Fadiel A, French B, Jhawar SR, Johnson DB, McKay RR, Rivera DR, Reuben DY, Shah S, Tinianov SL, Vinh DC, Mishra S, Warner JL.
Cancer Discov. 2021 Dec 10:candisc.1368.2021. doi: 10.1158/2159-8290.CD-21-1368. Online ahead of print.
Rapid pathogen-specific recruitment of immune effector cells in the skin by secreted toxins.
Nguyen TH, Cheung GYC, Rigby KM, Kamenyeva O, Kabat J, Sturdevant DE, Villaruz AE, Liu R, Piewngam P, Porter AR, Firdous S, Chiou J, Park MD, Hunt RL, Almufarriji FMF, Tan VY, Asiamah TK, McCausland JW, Fisher EL, Yeh AJ, Bae JS, Kobayashi SD, Wang JM, Barber DL, DeLeo FR, Otto M.
Nat Microbiol. 2021 Dec 6. doi: 10.1038/s41564-021-01012-9. Online ahead of print.
Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes.
Haliyur R, Walker JT, Sanyoura M, Reihsmann CV, Shrestha S, Aramandla R, Poffenberger G, Ramirez AH, Redick SD, Babon JAB, Prasad N, Hegele RA, Kent SC, Harlan DM, Bottino R, Philipson LH, Brissova M, Powers AC.
J Endocr Soc. 2021 Oct 29;5(12):bvab162. doi: 10.1210/jendso/bvab162. eCollection 2021 Dec 1.
Brief Report: The Characterization of Medical Comorbidity Prior to Autism Diagnosis in Children Before Age Two.
Eyoh EE, Failla MD, Williams ZJ, Schwartz KL, Cutting LE, Landman BA, Cascio CJ.
J Autism Dev Disord. 2021 Dec 1. doi: 10.1007/s10803-021-05380-3. Online ahead of print.