Megha Agarwal

All Publications

• Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation. bioRxiv : the preprint server for biology Metzl-Raz, E., Zhao, R., Deshpande, S., Powell, J., Porter, E. G., Zouaghi, Y., Liu, B. B., Kim, S. H., Abdi, I., Evergreen, I., Agarwal, M., Sheth, M. U., Rico, J., Miyamoto, M., Sanchez, J. M., Engreitz, J. M., Kundaje, A., Greenleaf, W. J., Gifford, C. A. 2025

  Abstract

  Defining the temporal gene regulatory programs that drive human organogenesis is essential for understanding the origins of congenital disease. We combined a time-resolved, single-cell multi-omic atlas of human iPSC-derived cardiac organoids with deep learning models that predict chromatin accessibility from DNA sequence, enabling the discovery of the regulatory syntax underlying early heart development. This framework uncovered cell-state-specific rules of cardiogenesis, including context-dependent activities of TEAD, HAND, and TBX transcription factor families, and linked these motifs to their target genes. We identified distinct programs guiding lineage divergence, such as ventricular versus pacemaker cardiomyocytes, and validated predictions by perturbing Myocardin (MYOCD), establishing its essential role in ventricular specification. Integration of chromatin, transcriptional, and genetic data further highlighted regulatory regions and disease-associated variants that perturb differentiation state transitions, supporting evidence that suggests congenital heart disease emerges early in development. This work bridges developmental gene regulation with disease genetics, providing a foundation for mechanistic and therapeutic insights into congenital diseases.

  View details for DOI 10.1101/2025.10.15.680997

  View details for PubMedID 41279701

  View details for PubMedCentralID PMC12632746

• Chicken Pulmonary MicroRNAs Targeting the PB2 (Segment 1) of Avian Influenza Virus ANIMAL RESEARCH AND ONE HEALTH Choudhary, A., Nidhishree, N. S., Pundir, R., Asaf, V., Mishra, A., Raut, A., Agarwal, M., Kumar, A. 2025

  View details for DOI 10.1002/aro2.70034

  View details for Web of Science ID 001610104600001

• The Wnt-pathway corepressor TLE3 interacts with the histone methyltransferase KMT1A to inhibit differentiation in Rhabdomyosarcoma. Oncogene Kalita, B., Sahu, S., Bharadwaj, A., Panneerselvam, L., Martinez-Cebrian, G., Agarwal, M., Mathew, S. J. 2024

  Abstract

  Rhabdomyosarcoma tumor cells resemble differentiating skeletal muscle cells, which unlike normal muscle cells, fail to undergo terminal differentiation, underlying their proliferative and metastatic properties. We identify the corepressor TLE3 as a key regulator of rhabdomyosarcoma tumorigenesis by inhibiting the Wnt-pathway. Loss of TLE3 function leads to Wnt-pathway activation, reduced proliferation, decreased migration, and enhanced differentiation in rhabdomyosarcoma cells. Muscle-specific TLE3-knockout results in enhanced expression of terminal myogenic differentiation markers during normal mouse development. TLE3-knockout rhabdomyosarcoma cell xenografts result in significantly smaller tumors characterized by reduced proliferation, increased apoptosis and enhanced differentiation. We demonstrate that TLE3 interacts with and recruits the histone methyltransferase KMT1A, leading to repression of target gene activation and inhibition of differentiation in rhabdomyosarcoma. A combination drug therapy regime to promote Wnt-pathway activation by the small molecule BIO and inhibit KMT1A by the drug chaetocin led to significantly reduced tumor volume, decreased proliferation, increased expression of differentiation markers and increased survival in rhabdomyosarcoma tumor-bearing mice. Thus, TLE3, the Wnt-pathway and KMT1A are excellent drug targets which can be exploited for treating rhabdomyosarcoma tumors.

  View details for DOI 10.1038/s41388-023-02911-3

  View details for PubMedID 38177411

  View details for PubMedCentralID 4462130

• TLE4 regulates muscle stem cell quiescence and skeletal muscle differentiation JOURNAL OF CELL SCIENCE Agarwal, M., Bharadwaj, A., Mathew, S. J. 2022; 135 (4)

  Abstract

  Muscle stem (satellite) cells express Pax7, a key transcription factor essential for satellite cell maintenance and adult muscle regeneration. We identify the corepressor transducin-like enhancer of split-4 (TLE4) as a Pax7 interaction partner expressed in quiescent satellite cells under homeostasis. A subset of satellite cells transiently downregulate TLE4 during early time points following muscle injury. We identify these to be activated satellite cells, and that TLE4 downregulation is required for Myf5 activation and myogenic commitment. Our results indicate that TLE4 represses Pax7-mediated Myf5 transcriptional activation by occupying the -111 kb Myf5 enhancer to maintain quiescence. Loss of TLE4 function causes Myf5 upregulation, an increase in satellite cell numbers and altered differentiation dynamics during regeneration. Thus, we have uncovered a novel mechanism to maintain satellite cell quiescence and regulate muscle differentiation mediated by the corepressor TLE4.

  View details for DOI 10.1242/jcs.256008

  View details for Web of Science ID 000762675900001

  View details for PubMedID 35099008