The role of SUV39H1 in maintaining heterochromatin architecture and identity in Acute Myeloid Leukemia

About This Grant

PROJECT SUMMARY: Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem cells (HSPCs) where normal 3D genome architectures are essential for proper lineage-specific functions. Repressive epigenetic features, such as Histone 3 Lysine 9 trimethylation (H3K9me3), play vital roles in maintaining healthy HSPCs, but we still understand very little about their roles in promoting AML. Marking constitutive heterochromatin, H3K9me3 is deposited by methyltransferases and participates in heterochromatin condensation; however, its significance in myeloid 3D genome architecture remains unclear. I identified SUV39H1, a key H3K9-specific methyltransferase, as a major depositor in AML cells, essential for sustaining proliferation and myeloid differentiation gene signatures. Moreover, in AML cells treated with DNA hypomethylating agents (HMAs), alterations in H3K9me3 distribution are observed. This suggests a potential role of SUV39H1, the major H3K9me3 depositor, in heterochromatin reorganization in the context of DNA hypomethylation. Together, I hypothesize that SUV39H1-mediated H3K9me3 shapes AML-associated nuclear architecture, and that the interplay between SUV39H1-driven H3K9me3 and DNA methylation status regulate heterochromatin integrity. To test this, I will profile leukemic transcriptomic programming and assay the high-order genome organization in SUV39H1-depleted AML cells to define the genomic mechanism in how SUV39H1 protect AML cells from differentiation in Aim 1. I will determine if SUV39H1 is necessary for AML cells to survive DNA hypomethylation by re-distributing H3K9me3 in Aim 2. This proposal seeks to investigate SUV39H1's role in preserving 3D genome architecture in AML cells and identify it as a potential therapeutic target to augment FDA-approved HMA therapy. If successful, this study will yield crucial insights into the determinants of 3D chromatin organization in AML. My ultimate career goal is to lead my own research team in genome and leukemia biology, driven by my personal experience as a leukemia patient. The successful completion of my proposed work hinges on mastering experimental methodologies and gaining in-depth knowledge in genomics and epigenetics. This expertise will empower me to achieve my goals. Dr. Feng Yue’s laboratory, with its extensive expertise in both leukemia biology and genome biology, is crucial for my training. By following the training plan outlined in this proposal, I will receive comprehensive training in various techniques, acquire essential knowledge, benefit from mentoring, and enhance my presentation skills. Conducting my research under the guidance and support of Dr. Yue ensures that I am on the right path to achieve my goals.