Lynette Chan

All Publications

• Chromatin topology control by a muscle-specific ribosomal protein. bioRxiv : the preprint server for biology Nakamura, M., Chen, X., Yao, S., Chan, L. X., Hongmei, R., Boulinguiez, A., Lally, N., Wu, H., Kodani, K., Hirose, K., Pirruccello, J., Malerba, A., Cheng, Y., Vedantham, V., Tan, L., Olgin, J. E., Lang, D., Huang, G. N. 2026

  Abstract

  Three-dimensional genome organization stabilizes cell-type-specific gene expression, yet the tissue-restricted factors that maintain chromatin insulation remain poorly understood. Here, we identify the muscle-specific ribosomal protein Rpl3l as an unexpected nuclear regulator of genome architecture in atrial cardiomyocytes. Rpl3l is enriched in the nucleus and nucleolus, where it binds its own genomic locus and stabilizes a CTCF-anchored chromatin boundary that represses the T-type calcium channel gene Cacna1h. Loss of Rpl3l weakens local chromatin insulation, increases long-range contacts across the Rpl3l-Cacna1h locus, derepresses Cacna1h, and increases susceptibility to atrial fibrillation (AF), which is suppressed by pharmacological inhibition of T-type calcium channels. Furthermore, AF-associated RPL3L variants exhibit impaired nucleolar localization, reduced rRNA binding, and defective repression of CACNA1H in human iPSC-derived atrial cardiomyocytes. Together, these findings reveal a ribosomal protein-chromatin axis linking genome insulation to ion-channel dosage control and cardiac rhythm stability, expanding the repertoire of cell-type-specific genome architecture regulators.

  View details for DOI 10.64898/2026.06.23.733628

  View details for PubMedID 42395400

  View details for PubMedCentralID PMC13320957

• Whole-genome 3D architectural screen reveals modulators of brain DNA structure. bioRxiv : the preprint server for biology Parasar, B., Venkatesh, A. R., Perera, J., Sosnick, L., Moghadami, S., Seo, Y., Shi, J., Chan, L., Takenawa, S., Akiyama, T., Sianto, O., Uenaka, T., Hadjipanayis, A., Wernig, M., Gitler, A. D., Tan, L. 2026

  Abstract

  Three-dimensional (3D) genome architecture is the foundation of gene regulation, and plays a critical role in normal physiology and disease. However, our understanding of its biochemical determinants has long been limited by technology: imaging-based screens only profile a small number of loci, while sequencing-based studies rarely exceed 100 samples or conditions. Here we present "in-plate chromosome conformation capture" (Plate-C), a high-throughput, cost-effective platform that profiles thousands of whole-genome architectures in a day. Plate-C enabled the first chemical screen for whole-genome structural changes-profiling 2,956 samples from 834 conditions across 5 neuronal and glial types, accompanied by 6,081 single cells using "easy diploid chromosome conformation capture" (Easy Dip-C) and 200,893 single-cell transcriptomes. We discovered that diverse, dose/time-dependent, and cell type/species-specific modes of DNA structural changes can be rapidly induced by manipulating epigenetic (HDAC, BET), metabolic (mTOR), proteostatic (UPR), developmental (GSK3/Wnt, Hedgehog), immune (cGAS/STING), and neurotransmission pathways. To validate our finding in vivo, we demonstrated in newborn mice that HDAC inhibition drives brain-wide genome rewiring within hours, highly correlated with changes in vitro and inducing a latent structural and transcriptional state orthogonal to normal differentiation. By enabling massively parallel profiling of whole-genome structures, Plate-C paves the way for systematic discovery of DNA folding principles to better understand and engineer the human genome in 3D.

  View details for DOI 10.64898/2026.04.15.718501

  View details for PubMedID 42039500

  View details for PubMedCentralID PMC13104906

• Transcription factor antagonism regulates heterogeneity in embryonic stem cell states MOLECULAR CELL Hu, S., Metcalf, E., Mahat, D., Chan, L., Sohal, N., Chakraborty, M., Hamilton, M., Singh, A., Singh, A., Lees, J. A., Sharp, P. A., Garg, S. 2022; 82 (23): 4410-+

  Abstract

  Gene expression heterogeneity underlies cell states and contributes to developmental robustness. While heterogeneity can arise from stochastic transcriptional processes, the extent to which it is regulated is unclear. Here, we characterize the regulatory program underlying heterogeneity in murine embryonic stem cell (mESC) states. We identify differentially active and transcribed enhancers (DATEs) across states. DATEs regulate differentially expressed genes and are distinguished by co-binding of transcription factors Klf4 and Zfp281. In contrast to other factors that interact in a positive feedback network stabilizing mESC cell-type identity, Klf4 and Zfp281 drive opposing transcriptional and chromatin programs. Abrogation of factor binding to DATEs dampens variation in gene expression, and factor loss alters kinetics of switching between states. These results show antagonism between factors at enhancers results in gene expression heterogeneity and formation of cell states, with implications for the generation of diverse cell types during development.

  View details for DOI 10.1016/j.molcel.2022.10.022

  View details for Web of Science ID 000922730600005

  View details for PubMedID 36356583

  View details for PubMedCentralID PMC9722640