Sander Lab

Understanding and Reversing Pancreatic Beta Cell Dysfunction in Diabetes

Matthew Wortham, Ph.D.

Assistant Adjunct Professor

I received my Ph.D. in Pathology from Duke University, where I worked in the lab of Dr. Hai Yan to characterize the role of the homeobox transcription factor Otx2 in hindbrain development and neoplasia. In the Sander lab, the goal of my research is to define the mechanisms whereby beta cells detect and respond to changes in their metabolic environment. Prolonged changes in energy balance alter insulin demand and evoke coordinate adaptations of the insulin secretory response. Ongoing work in the lab has implicated posttranslational chromatin modifications in the dynamic adjustment of insulin secretion by the beta cell. These results have led to the working model that sustained changes in nutrient state are detected by chromatin-modifying enzymes, leading to altered gene expression and adaptive insulin secretion. To build upon these findings, I apply genomics, metabolomics, and classical islet techniques to address the following questions:

  1.  How is chromatin state in the beta cell regulated by the two extremes of energy balance: prolonged fasting and obesity?
  2. How does chromatin reorganization contribute to beta cell functional plasticity?
  3. Does defective chromatin remodeling underlie beta cell failure during diabetes pathogenesis?
  4. On a shorter timescale, how do biological rhythms (e.g. circadian clock and fasting/feeding) entrain the insulin secretory response?

 

Publications

Ibarra Urizar A, Prause M, Ingerslev L, Wortham M, Sui Y, Sander M, Williams K, Barrès R, Larsen M, Christensen GL, Billestrup N. Beta cell dysfunction induced by Bone Morphogenetic Protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding. Cell Death Dis, in press.

Wortham M*, Liu F, Harrington AR, Fleischman JY, Wallace M, Mulas F, Mallick M, Vinckier NK, Cross BR, Chiou J, Patel NA, Sui Y, McGrail C, Jun Y, Wang G, Jhala US, Schüle R, Shirihai OS, Huising MO, Gaulton KJ, Metallo CM, Sander M*. Nutrient regulation of the islet epigenome controls adaptive insulin secretion. J Clin Invest. 2023 Apr;133(8):e165208. *corresponding authors.

Commentary:     Aamodt KI, Powers AC. Peeling the onion: another layer in the regulation of insulin secretion. J Clin Invest. 2023 Apr;133(8):e169718.

Ramms B, Pollow DP, Zhu H, Nora C, Harrington AR, Omar I, Gordts PLSM, Wortham M*, Sander M*. Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity. Diabetes. 2022 Dec;71(12):2513-2529. *corresponding authors.

Nguyen-Ngoc KV, Wortham M, and Sander M. Sizing up beta cells made from stem cells. Nat Biotechnol. 2022 Jul;40(7):1006-1008.

Shum M, Segawa M, Gharakhanian R, Viñuela A, Wortham M, Baghdasarian S, Wolf DM, Sereda SB, Nocito L, Stiles L, Zhou Z, Gutierrez V, Sander M, Shirihai OS, Liesa M. Deletion of ABCB10 in β-cells protects from high-fat diet induced insulin resistance. Mol Metab. 2021 Nov;22:101403.

Parashar S, Chidambaram R, Chen S, Liem CR, Griffis E, Lambert GG, Shaner NC, Wortham M, Hay JC, Ferro-Novick S. Endoplasmic reticulum tubules limit the size of misfolded protein condensates. eLife. 2021 Sep;10:e71642.

Wortham M, and Sander M. Transcriptional mechanisms of pancreatic β-cell maturation and functional adaptation. Trends Endocrinol Metab. 2021 Jul;32(7):474-87.

Vinckier NK*, Patel NA*, Geusz RJ*, Wang A, Wang J, Matta I, Harrington AR, Wortham M, Wetton N, Wang J, Jhala US, Rosenfeld MG, Benner CW, Shih HP, Sander M. LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development. Nat Commun. 2020 April;11:2082. *equal contribution.

Ibarra Urizar A, Prause M, Wortham M, Sui Y, Thams P, Sander M, Christensen GL, Billestrup N. β-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1β is associated with changes in expression of β-cell maturity genes and associated histone modifications. Mol Cell Endocrinol. 2019 Jul;496:110524.

Wortham M*, Benthuysen JR*, Wallace M, Savas JN, Mulas F, Divakaruni A, Liu F, Albert V, Taylor BL, Sui Y, Saez E, Murphy A, Yates JR, Metallo CM, Sander M. Integrated in vivo quantitative proteomics and nutrient tracing reveals age-related metabolic rewiring of pancreatic β-cell function. Cell Rep. 2018 Dec;25(10):2904-2918.e8. *equal contributors.

Gaetani R, Aouad S, Demaddalena L, Straessle H, Dzieciatkowska M, Wortham M, Bender H, Nguyen-Ngoc K, Schmid-Schoenbein G, George S, Hughes C, Sander M, Hansen K, Christman K. (2018). Evaluation of different decellularization protocols on the generation of pancreas-derived hydrogel. Tissue Engineering, 24, 697-708.

Wortham M and Sander M. (2016) Mechanisms of β-cell functional adaptation to changes in workload. Diabetes Obes Metab 18 (Suppl. 1), 78-86.

Wortham M and Sander, M. (2016) High-T gives beta cells a boost. Cell Metabolism 23: 761-763.

Wortham M*, Guo C*, Zhang MM, Song L, Lee B-K, Iyer VI, Furey TS, Crawford GE, He Y, and Yan H. (2014) Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma. PLoS One (9)e107156. *equal contributors

Guo C*, Chang CC*, Wortham M, Chen LH, Kernagis DN, Qin J, Cho YW, Chi JT, Grant GA, McLendon RE, Yan H, Ge K, Papadopolous N, Bigner DD, and He Y. (2012) Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways. PNAS 109(43): 17603-08. *equal contributors

Shibata Y, Sheffield NC, Fedrigo O, Babbitt CC, Wortham M, Tewari AK, London D, Song L, Lee BK, Iyer VR, Parker SCJ, Margulies EH, Wray GA, Furey TS, and Crawford GE. (2012) Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection. PLoS Genet. 8(6): e1002789.

Wortham M, Jin G, Sun JL, Bigner DD, He Y, and Yan H. (2012) Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells. PLoS One 7(4): e36211.

Adamson DC*, Shi Q*, Wortham M*, Northcott PA, Di C, Duncan CG, Li J, McLendon RE, Bigner DD, Taylor MD, and Yan H. (2010) OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res. 70(1): 181-91. *equal contributors

Wortham M, He L, Gyamfi M, Copple BL, and Wan YJ. (2008) The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. Dig Dis Sci. 53(10): 2761-74.

Wortham M, Czerwinski M, He L, Parkinson A, and Wan YJ. (2007) Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver. Drug Metab Dispos. 35(9): 1700-10.