Critical roles of Ikaros and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

Ding, Y.; He, B.; Bogush, D.; Schramm, J.; Singh, C.; Dovat, K.; Randazzo, J.; Tukaramrao, D.; Hengst, J.; Annageldiyev, C.; Kudva, A.; Desai, D.; Sharma, A.; Spiegelman, V. S.; Huang, S.; Viet, C. T.; Dorsam, G.; Saulnier Scholler, G.; Broach, J.; Yue, F.; Dovat, S.

doi:10.1101/2024.06.27.600861

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bioRxiv · 10.1101/2024.06.27.600861

Critical roles of Ikaros and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

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Abstract

The IKZF1 gene encodes IKAROS - a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which Ikaros exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of Ikaros and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel Ikaros and HDAC1 functions in T-ALL: Both Ikaros and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by Ikaros is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and Ikaros-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of Ikaros and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

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Ding, Y., He, B., Bogush, D., Schramm, J., Singh, C., Dovat, K., Randazzo, J., Tukaramrao, D., Hengst, J., Annageldiyev, C., Kudva, A., Desai, D., Sharma, A., Spiegelman, V. S., Huang, S., Viet, C. T., Dorsam, G., Saulnier Scholler, G., Broach, J., Yue, F., Dovat, S.. 2024-07-02. Critical roles of Ikaros and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia. https://doi.org/10.1101/2024.06.27.600861

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