Background: The goal of this proposal is to elucidate epigenetic mechanisms regulated by the high mobility group A1 (Hmga1) chromatin remodeling protein in hematopoietic stem cells (HSC) and to determine how this changes with aging. Hmga1 modulates gene expression by ?opening? chromatin and recruiting transcriptional complexes to DNA. While it is clear that alterations in the epigenome and transcriptional networks occur with aging in HSC, the key factors that drive aging phenotypes remain poorly understood. Here, we focus on the Hmga1 chromatin regulator as a key regulator of ?youthful? HSC function. Our scientific premise is based on the following preliminary results: 1) Hmga1 expression is enriched in HSC and declines with aging, 2) Mice with global deletion of Hmga1 develop premature aging phenotypes, 3) Hmga1 deficient HSC recapitulate a subset of aging phenotypes, including decreased differentiation to pre- B lymphoid cells in vitro and poor regenerative function in serial bone marrow transplantation (BMT) in vivo. 4) In published work, we discovered that HMGA1: A) maintains a de-differentiated, pluripotent state in human embryonic stem cells by inducing stem cell transcriptional networks, and, B) enhances reprogramming of somatic cells to pluripotent stem cells by the Yamanaka factors. 5) More recently, we uncovered a novel role for HMGA1 as a master regulator of the intestinal stem cell compartment by amplifying Wnt/?-catenin signaling. 6) Published work from our group also demonstrates that de-regulated expression of HMGA1 causes a block in differentiation and clonal expansion in hematopoietic cells. These intriguing results support the hypotheses that: 1) Hmga1 is required by ?youthful? HSC for balanced differentiation and regenerative function, 2) Hmga1 orchestrates the assembly of active transcriptional complexes to induce expression of genes required for lymphoid development and regeneration, 3) Hmga1 loss with aging disrupts the epigenome, alters gene expression, and impairs HSC function, 4) Identifying epigenetic changes mediated by Hmga1 will reveal pathways that could be modulated to counter aging phenotypes.
Aims /Approach: To test this, we now propose the following Single Aim for the SHINE II Initiative to stimulate new directions in hematology research: To elucidate epigenetic mechanisms which mediate Hmga1 functions in ?youthful? HSC. A) To dissect the role of Hmga1 in HSC, we will perform in vitro functional assays and competitive BMT with HSC wildtype or null for Hmga1, B) To identify epigenetic alterations and developmental pathways governed by Hmga1 in HSC, we will integrate results from ATAC-seq, RNA-seq, and ChIP-seq. Impact: We expect to identify specific epigenetic marks and mechanistic pathways mediated by Hmga1 in ?youthful? HSC. This work could challenge the existing paradigm that aging in HSC is irreversible and lead to novel clinical approaches to modulate epigenetic pathways induced by Hmga1 to restore regenerative function in aging HSC and possibly other adult stem cells.
Blood stem cells have the remarkable capability of generating blood for our entire lifespan, although their function declines with aging. We are studying: 1) regulatory factors that enable ?youthful? blood stem cells to generate blood, and, 2) how this process changes with aging. A better understanding of aging in stem cells could lead to the discovery of clinical approaches to reverse some aspects of aging as well as new treatments for diseases that affect the function of blood stem cells.
|Carleton, Neil M; Zhu, Guangjing; Gorbounov, Mikhail et al. (2018) PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis. Prostate 78:547-559|