Institute Affiliations

All Publications

  • Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy. European heart journal Perea-Gil, I., Seeger, T., Bruyneel, A. A., Termglinchan, V., Monte, E., Lim, E. W., Vadgama, N., Furihata, T., Gavidia, A. A., Arthur Ataam, J., Bharucha, N., Martinez-Amador, N., Ameen, M., Nair, P., Serrano, R., Kaur, B., Feyen, D. A., Diecke, S., Snyder, M. P., Metallo, C. M., Mercola, M., Karakikes, I. 2022


    AIMS: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro.METHODS AND RESULTS: Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Go 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 (ATF4) and its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions.CONCLUSIONS: A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM.

    View details for DOI 10.1093/eurheartj/ehac305

    View details for PubMedID 35728000

  • A cancer-associated RNA polymerase III identity drives robust transcription and expression of snaR-A noncoding RNA. Nature communications Van Bortle, K., Marciano, D. P., Liu, Q., Chou, T., Lipchik, A. M., Gollapudi, S., Geller, B. S., Monte, E., Kamakaka, R. T., Snyder, M. P. 2022; 13 (1): 3007


    RNA polymerase III (Pol III) includes two alternate isoforms, defined by mutually exclusive incorporation of subunit POLR3G (RPC7alpha) or POLR3GL (RPC7beta), in mammals. The contributions of POLR3G and POLR3GL to transcription potential has remained poorly defined. Here, we discover that loss of subunit POLR3G is accompanied by a restricted repertoire of genes transcribed by Pol III. Particularly sensitive is snaR-A, a small noncoding RNA implicated in cancer proliferation and metastasis. Analysis of Pol III isoform biases and downstream chromatin features identifies loss of POLR3G and snaR-A during differentiation, and conversely, re-establishment of POLR3G gene expression and SNAR-A gene features in cancer contexts. Our results support a model in which Pol III identity functions as an important transcriptional regulatory mechanism. Upregulation of POLR3G, which is driven by MYC, identifies a subgroup of patients with unfavorable survival outcomes in specific cancers, further implicating the POLR3G-enhanced transcription repertoire as a potential disease factor.

    View details for DOI 10.1038/s41467-022-30323-6

    View details for PubMedID 35637192

  • Epigenomic Disruption of Cardiovascular Care What It Will Take CIRCULATION RESEARCH Monte, E., Fischer, M. A., Vondriska, T. M. 2017; 120 (11): 1692–93

    View details for PubMedID 28546346

    View details for PubMedCentralID PMC5527682