Heankel Lyons

All Publications

• Transcription regulation by biomolecular condensates. Nature reviews. Molecular cell biology Pei, G., Lyons, H., Li, P., Sabari, B. R. 2025; 26 (3): 213-236

  Abstract

  Biomolecular condensates regulate transcription by dynamically compartmentalizing the transcription machinery. Classic models of transcription regulation focus on the recruitment and regulation of RNA polymerase II by the formation of complexes at the 1-10 nm length scale, which are driven by structured and stoichiometric interactions. These complexes are further organized into condensates at the 100-1,000 nm length scale, which are driven by dynamic multivalent interactions often involving domain-ligand pairs or intrinsically disordered regions. Regulation through condensate-mediated organization does not supersede the processes occurring at the 1-10 nm scale, but it provides regulatory mechanisms for promoting or preventing these processes in the crowded nuclear environment. Regulation of transcription by transcriptional condensates is involved in cell state transitions during animal and plant development, cell signalling and cellular responses to the environment. These condensate-mediated processes are dysregulated in developmental disorders, cancer and neurodegeneration. In this Review, we discuss the principles underlying the regulation of transcriptional condensates, their roles in physiology and their dysregulation in human diseases.

  View details for DOI 10.1038/s41580-024-00789-x

  View details for PubMedID 39516712

  View details for PubMedCentralID 3640494

• The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators. Molecular cell Ahn, J. H., Guo, Y., Lyons, H., Mackintosh, S. G., Lau, B. K., Edmondson, R. D., Byrum, S. D., Storey, A. J., Tackett, A. J., Cai, L., Sabari, B. R., Wang, G. G. 2025; 85 (4): 708-725.e9

  Abstract

  Recurrent cancer-causing fusions of NUP98 produce higher-order assemblies known as condensates. How NUP98 oncofusion-driven condensates activate oncogenes remains poorly understood. Here, we investigate NUP98-PHF23, a leukemogenic chimera of the disordered phenylalanine-and-glycine (FG)-repeat-rich region of NUP98 and the H3K4me3/2-binding plant homeodomain (PHD) finger domain of PHF23. Our integrated analyses using mutagenesis, proteomics, genomics, and condensate reconstitution demonstrate that the PHD domain targets condensate to the H3K4me3/2-demarcated developmental genes, while FG repeats determine the condensate composition and gene activation. FG repeats are necessary to form condensates that partition a specific set of transcriptional regulators, notably the KMT2/MLL H3K4 methyltransferases, histone acetyltransferases, and BRD4. FG repeats are sufficient to partition transcriptional regulators and activate a reporter when tethered to a genomic locus. NUP98-PHF23 assembles the chromatin-bound condensates that partition multiple positive regulators, initiating a feedforward loop of reading-and-writing the active histone modifications. This network of interactions enforces an open chromatin landscape at proto-oncogenes, thereby driving cancerous transcriptional programs.

  View details for DOI 10.1016/j.molcel.2024.12.026

  View details for PubMedID 39922194

• Coactivator condensation drives cardiovascular cell lineage specification SCIENCE ADVANCES Gan, P., Eppert, M., de la Cruz, N., Lyons, H., Shah, A. M., Veettil, R. T., Chen, K., Pradhan, P., Bezprozvannaya, S., Xu, L., Liu, N., Olson, E. N., Sabari, B. R. 2024; 10 (11): eadk7160

  Abstract

  During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here, we show that the cardiovascular transcriptional coactivator myocardin (MYOCD) activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The carboxyl-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region's ability to form condensates disrupts gene activation and smooth muscle cell reprogramming. Rescuing condensate formation by replacing this region with disordered regions from functionally unrelated proteins rescues gene activation and smooth muscle cell reprogramming. Our findings demonstrate that MYOCD condensate formation is required for gene activation during cardiovascular differentiation. We propose that the formation of transcriptional condensates at critical concentrations of cell type-specific regulators provides a molecular switch underlying the activation of key cell identity genes during development.

  View details for DOI 10.1126/sciadv.adk7160

  View details for Web of Science ID 001190089500002

  View details for PubMedID 38489358

  View details for PubMedCentralID PMC10942106

• Functional partitioning of transcriptional regulators by patterned charge blocks. Cell Lyons, H., Veettil, R. T., Pradhan, P., Fornero, C., De La Cruz, N., Ito, K., Eppert, M., Roeder, R. G., Sabari, B. R. 2023; 186 (2): 327-345.e28

  Abstract

  Components of transcriptional machinery are selectively partitioned into specific condensates, often mediated by protein disorder, yet we know little about how this specificity is achieved. Here, we show that condensates composed of the intrinsically disordered region (IDR) of MED1 selectively partition RNA polymerase II together with its positive allosteric regulators while excluding negative regulators. This selective compartmentalization is sufficient to activate transcription and is required for gene activation during a cell-state transition. The IDRs of partitioned proteins are necessary and sufficient for selective compartmentalization and require alternating blocks of charged amino acids. Disrupting this charge pattern prevents partitioning, whereas adding the pattern to proteins promotes partitioning with functional consequences for gene activation. IDRs with similar patterned charge blocks show similar partitioning and function. These findings demonstrate that disorder-mediated interactions can selectively compartmentalize specific functionally related proteins from a complex mixture of biomolecules, leading to regulation of a biochemical pathway.

  View details for DOI 10.1016/j.cell.2022.12.013

  View details for PubMedID 36603581

  View details for PubMedCentralID PMC9910284

• Anterograde transneuronal tracing and genetic control with engineered yellow fever vaccine YFV-17D. Nature methods Li, E., Guo, J., Oh, S. J., Luo, Y., Oliveros, H. C., Du, W., Arano, R., Kim, Y., Chen, Y. T., Eitson, J., Lin, D. T., Li, Y., Roberts, T., Schoggins, J. W., Xu, W. 2021; 18 (12): 1542-1551

  Abstract

  Transneuronal viruses are powerful tools for tracing neuronal circuits or delivering genes to specific neurons in the brain. While there are multiple retrograde viruses, few anterograde viruses are available. Further, available anterograde viruses often have limitations such as retrograde transport, high neuronal toxicity or weak signals. We developed an anterograde viral system based on a live attenuated vaccine for yellow fever-YFV-17D. Replication- or packaging-deficient mutants of YFV-17D can be reconstituted in the brain, leading to efficient synapse-specific and anterograde-only transneuronal spreading, which can be controlled to achieve either monosynaptic or polysynaptic tracing. Moreover, inducible transient replication of YFV-17D mutant is sufficient to induce permanent transneuronal genetic modifications without causing neuronal toxicity. The engineered YFV-17D systems can be used to express fluorescent markers, sensors or effectors in downstream neurons, thus providing versatile tools for mapping and functionally controlling neuronal circuits.

  View details for DOI 10.1038/s41592-021-01319-9

  View details for PubMedID 34824475

  View details for PubMedCentralID PMC8665090