Heankel Lyons

All Publications

• KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. JCI insight Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L., Lyons, H., Molotsky, E., Bombosch, J. S., Sianto, O., Ross, J. P., Hoang, P., Zhao, L., Spencer, C., Sumner, C. J., Monje, M., Day, J. W., Gitler, A. D. 2026

  Abstract

  Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

  View details for DOI 10.1172/jci.insight.197941

  View details for PubMedID 41885937

• Sequence-based prediction of condensate composition reveals that specificity can emerge from multivalent interactions among disordered regions. bioRxiv : the preprint server for biology Wessén, J., De La Cruz, N., Lyons, H., Chan, H. S., Sabari, B. R. 2025

  Abstract

  While specificity of biomolecular interactions is typically understood to require interactions involving ordered structures, several biomolecular condensates exhibit specificity in the absence of apparent structural order. We have previously shown that condensates composed of the disordered region of MED1 partition specific proteins, mediated by sequence patterns of charged amino acids on the disordered regions of both MED1 and the interacting partner. Whether this specificity is due to an unknown ordered-structure-mediated interaction or from the dynamic multivalent interactions between the patterned charged amino acids in the disordered regions was unresolved. Here we show that a polymer physics-based model that only accounts for multivalent interactions among polymers in a statistical manner can largely explain published data on selective partitioning and make predictions that are subsequently experimentally validated. These results suggest that the specificity of condensate composition is underpinned to a substantial extent by multivalent interactions in the context of conformational disorder.

  View details for DOI 10.1101/2025.06.13.659429

  View details for PubMedID 40667294

  View details for PubMedCentralID PMC12262440

• RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates. Cell Lyons, H., Pradhan, P., Prakasam, G., Vashishtha, S., Li, X., Eppert, M., Fornero, C., Tcheuyap, V. T., McGlynn, K., Yu, Z., Raju, D. R., Koduru, P. R., Xing, C., Kapur, P., Brugarolas, J., Sabari, B. R. 2025; 188 (14): 3843-3862.e28

  Abstract

  Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of DNA-binding oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate specificity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of disease genetics in investigating relationships between condensate specificity and function.

  View details for DOI 10.1016/j.cell.2025.04.002

  View details for PubMedID 40286793

  View details for PubMedCentralID PMC12255532

• 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