Christy Luong

All Publications

• Escape from X inactivation is directly modulated by levels of Xist non-coding RNA. bioRxiv : the preprint server for biology Hauth, A., Panten, J., Kneuss, E., Picard, C., Servant, N., Rall, I., Perez-Rico, Y. A., Clerquin, L., Servaas, N., Villacorta, L., Jung, F., Luong, C., Chang, H. Y., Zaugg, J. B., Stegle, O., Odom, D. T., Loda, A., Heard, E. 2024

  Abstract

  In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in a process mediated by the non-coding RNA Xist1. Here, we demonstrate that Xist can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, we show that Xist has the capacity to actively silence genes that escape XCI both in neuronal progenitor cells (NPCs) and in vivo, in mouse embryos. We also show that Xist plays a direct role in eliminating TAD-like structures associated with clusters of escapee genes on the inactive X chromosome, and that this is dependent on Xist's XCI initiation partner, SPEN2. We further demonstrate that Xist's function in suppressing gene expression of escapees and topological domain formation is reversible for up to seven days post-induction, but that sustained Xist up-regulation leads to progressively irreversible silencing and CpG island DNA methylation of facultative escapees. Thus, the distinctive transcriptional and regulatory topologies of the silenced X chromosome is actively, directly - and reversibly - controlled by Xist RNA throughout life.

  View details for DOI 10.1101/2024.02.22.581559

  View details for PubMedID 38559194

• DNA-guided transcription factor cooperativity shapes face and limb mesenchyme. Cell Kim, S., Morgunova, E., Naqvi, S., Goovaerts, S., Bader, M., Koska, M., Popov, A., Luong, C., Pogson, A., Swigut, T., Claes, P., Taipale, J., Wysocka, J. 2024

  Abstract

  Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how "Coordinator," a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.

  View details for DOI 10.1016/j.cell.2023.12.032

  View details for PubMedID 38262408

• DNA-guided transcription factor cooperativity shapes face and limb mesenchyme. bioRxiv : the preprint server for biology Kim, S., Morgunova, E., Naqvi, S., Bader, M., Koska, M., Popov, A., Luong, C., Pogson, A., Claes, P., Taipale, J., Wysocka, J. 2023

  Abstract

  Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how 'Coordinator', a long DNA motif comprised of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, while HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in shared regulation of genes involved in cell-type and positional identities, and ultimately shapes facial morphology and evolution.

  View details for DOI 10.1101/2023.05.29.541540

  View details for PubMedID 37398193

  View details for PubMedCentralID PMC10312427

• Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases. Cell genomics Wang, S. K., Nair, S., Li, R., Kraft, K., Pampari, A., Patel, A., Kang, J. B., Luong, C., Kundaje, A., Chang, H. Y. 2022; 2 (8)

  Abstract

  Genome-wide association studies (GWASs) of eye disorders have identified hundreds of genetic variants associated with ocular disease. However, the vast majority of these variants are noncoding, making it challenging to interpret their function. Here we present a joint single-cell atlas of gene expression and chromatin accessibility of the adult human retina with more than 50,000 cells, which we used to analyze single-nucleotide polymorphisms (SNPs) implicated by GWASs of age-related macular degeneration, glaucoma, diabetic retinopathy, myopia, and type 2 macular telangiectasia. We integrate this atlas with a HiChIP enhancer connectome, expression quantitative trait loci (eQTL) data, and base-resolution deep learning models to predict noncoding SNPs with causal roles in eye disease, assess SNP impact on transcription factor binding, and define their known and novel target genes. Our efforts nominate pathogenic SNP-target gene interactions for multiple vision disorders and provide a potentially powerful resource for interpreting noncoding variation in the eye.

  View details for DOI 10.1016/j.xgen.2022.100164

  View details for PubMedID 36277849

• Xist nucleates local protein gradients to propagate silencing across the X chromosome CELL Markaki, Y., Chong, J., Wang, Y., Jacobson, E. C., Luong, C., Tan, S. X., Jachowicz, J. W., Strehle, M., Maestrini, D., Banerjee, A. K., Mistry, B. A., Dror, I., Dossin, F., Schoeneberg, J., Heard, E., Guttman, M., Chou, T., Plath, K. 2021; 184 (25): 6174-+

  Abstract

  The lncRNA Xist forms ∼50 diffraction-limited foci to transcriptionally silence one X chromosome. How this small number of RNA foci and interacting proteins regulate a much larger number of X-linked genes is unknown. We show that Xist foci are locally confined, contain ∼2 RNA molecules, and nucleate supramolecular complexes (SMACs) that include many copies of the critical silencing protein SPEN. Aggregation and exchange of SMAC proteins generate local protein gradients that regulate broad, proximal chromatin regions. Partitioning of numerous SPEN molecules into SMACs is mediated by their intrinsically disordered regions and essential for transcriptional repression. Polycomb deposition via SMACs induces chromatin compaction and the increase in SMACs density around genes, which propagates silencing across the X chromosome. Our findings introduce a mechanism for functional nuclear compartmentalization whereby crowding of transcriptional and architectural regulators enables the silencing of many target genes by few RNA molecules.

  View details for DOI 10.1016/j.cell.2021.10.022

  View details for Web of Science ID 000730753900003

  View details for PubMedID 34813726

  View details for PubMedCentralID PMC8671326