Selin Jessa

All Publications

• K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas NATURE GENETICS Jessa, S., Mohammadnia, A., Harutyunyan, A. S., Hulswit, M., Varadharajan, S., Lakkis, H., Kabir, N., Bashardanesh, Z., Hebert, S., Faury, D., Vladoiu, M. C., Worme, S., Coutelier, M., Krug, B., Faria Andrade, A., Pathania, M., Bajic, A., Weil, A. G., Ellezam, B., Atkinson, J., Dudley, R. R., Farmer, J., Perreault, S., Garcia, B. A., Larouche, V., Blanchette, M., Garzia, L., Bhaduri, A., Ligon, K. L., Bandopadhayay, P., Taylor, M. D., Mack, S. C., Jabado, N., Kleinman, C. L. 2022; 54 (12): 1865-1880

  Abstract

  Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate.

  View details for DOI 10.1038/s41588-022-01205-w

  View details for Web of Science ID 000920296200015

  View details for PubMedID 36471070

  View details for PubMedCentralID PMC9742294

• Histone H3.3G34-Mutant Intemeuron Progenitors Co-opt PDGFRA for Gliomagenesis CELL Chen, C. L., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A., Faury, D., Jawhar, W., Dali, R., Suzuki, H., Pathania, M., Deli, A., Dubois, F., Woodward, E., Hebert, S., Coutelier, M., Karamchandani, J., Albrecht, S., Brandner, S., De Jay, N., Gayden, T., Bajic, A., Harutyunyan, A. S., Marchione, D. M., Mikael, L. G., Juretic, N., Zeinieh, M., Russo, C., Maestro, N., Bassenden, A., Hauser, P., Virga, J., Bognar, L., Klekner, A., Zapotocky, M., Vicha, A., Krskova, L., Vanova, K., Zamecnik, J., Sumerauer, D., Ekert, P. G., Ziegler, D. S., Ellezam, B., Filbin, M. G., Blanchette, M., Hansford, J. R., Dong-Anh Khuong-Quang, Berghuis, A. M., Weil, A. G., Garcia, B. A., Garzia, L., Mack, S. C., Beroukhim, R., Ligon, K. L., Taylor, M. D., Bandopadhayay, P., Kramm, C., Pfister, S. M., Korshunov, A., Sturm, D., Jones, D., Salomoni, P., Kleinman, C. L., Jabado, N. 2020; 183 (6): 1617-+

  Abstract

  Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.

  View details for DOI 10.1016/j.cell.2020.11.012

  View details for Web of Science ID 000597929400015

  View details for PubMedID 33259802

  View details for PubMedCentralID PMC7791404

• Stalled developmental programs at the root of pediatric brain tumors NATURE GENETICS Jessa, S., Blanchet-Cohen, A., Krug, B., Vladoiu, M., Coutelier, M., Faury, D., Poreau, B., De Jay, N., Hebert, S., Monlong, J., Farmer, W., Donovan, L. K., Hu, Y., McConechy, M. K., Cavalli, F. G., Mikael, L. G., Ellezam, B., Richer, M., Allaire, A., Weil, A. G., Atkinson, J., Farmer, J., Dudley, R. R., Larouche, V., Crevier, L., Albrecht, S., Filbin, M. G., Sartelet, H., Lutz, P., Nagy, C., Turecki, G., Costantino, S., Dirks, P. B., Murai, K. K., Bourque, G., Ragoussis, J., Garzia, L., Taylor, M. D., Jabado, N., Kleinman, C. L. 2019; 51 (12): 1702-+

  Abstract

  Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

  View details for DOI 10.1038/s41588-019-0531-7

  View details for Web of Science ID 000499696700007

  View details for PubMedID 31768071

  View details for PubMedCentralID PMC6885128

• Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function NATURE COMMUNICATIONS Andrade, A., Annett, A., Karimi, E., Topouza, D., Rezanejad, M., Liu, Y., McNicholas, M., Santiago, E., Llivichuzhca-Loja, D., Gehlhaar, A., Jessa, S., De Cola, A., Chandarana, B., Russo, C., Faury, D., Danieau, G., Puligandla, E., Wei, Y., Zeinieh, M., Wu, Q., Hebert, S., Juretic, N., Nakada, E. M., Krug, B., Larouche, V., Weil, A. G., Dudley, R. R., Karamchandani, J., Agnihotri, S., Quail, D. F., Ellezam, B., Konnikova, L., Walsh, L. A., Pathania, M., Kleinman, C. L., Jabado, N. 2024; 15 (1): 7769

  Abstract

  Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.

  View details for DOI 10.1038/s41467-024-52096-w

  View details for Web of Science ID 001307964900029

  View details for PubMedID 39237515

  View details for PubMedCentralID PMC11377583

• chromswitch: a flexible method to detect chromatin state switches BIOINFORMATICS Jessa, S., Kleinman, C. L. 2018; 34 (13): 2286-2288

  Abstract

  Chromatin state plays a major role in controlling gene expression, and comparative analysis of ChIP-seq data is key to understanding epigenetic regulation. We present chromswitch, an R/Bioconductor package to integrate epigenomic data in a defined window of interest to detect an overall switch in chromatin state. Chromswitch accurately classifies a benchmarking dataset, and when applied genome-wide, the tool successfully detects chromatin changes that result in brain-specific expression.Chromswitch is implemented as an R package available from Bioconductor at https://bioconductor.org/packages/chromswitch. All data and code for reproducing the analysis presented in this paper are available at https://doi.org/10.5281/zenodo.1101260.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/bty075

  View details for Web of Science ID 000438247800082

  View details for PubMedID 29438498

  View details for PubMedCentralID PMC6022667