{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KDM1A, also known as LSD1, is a versatile histone demethylase that plays a central role in modulating chromatin structure and gene expression. Initially characterized for its ability to remove methyl groups from histone H3 lysine 4 (H3K4) – a mark associated with active transcription – KDM1A functions as a transcriptional corepressor in many contexts by erasing these activating marks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, KDM1A is an integral component of multiprotein complexes, such as those containing CoREST and REST, and is scaffolded by long noncoding RNAs (e.g. HOTAIR) to coordinate the recruitment of distinct histone modification activities on chromatin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Beyond its repressive functions, KDM1A can also act as a transcriptional activator: for example, when associated with the androgen receptor, it demethylates repressive marks (H3K9) to promote the expression of androgen-responsive genes, thereby contributing to cell proliferation in the context of prostate cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, KDM1A targets non-histone substrates such as p53, where its demethylase activity modulates p53’s interaction with coactivators and consequently represses p53-mediated apoptotic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Its activity is also critical during development; for instance, KDM1A ensures proper gastrulation in mice by demethylating factors that affect the stability of DNA methyltransferase 1, thereby linking histone and DNA methylation pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and it is necessary for the decommissioning of enhancers during embryonic stem cell differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of disease, aberrant KDM1A activity has been implicated in oncogenesis. For example, in MLL-rearranged leukemia, KDM1A sustains oncogenic transcriptional programs and maintains the differentiation block in leukemia stem cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while overexpression of KDM1A in various solid tumors correlates with increased cell proliferation and aggressive disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Remarkably, dysregulated KDM1A activity can also have transgenerational effects; its overexpression during spermatogenesis leads to reduced H3K4 methylation in sperm and consequent epigenetic inheritance of developmental defects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies highlight the multifunctional and context-dependent nature of KDM1A. By dynamically regulating both activating and repressive chromatin marks on histones and non-histone proteins, KDM1A is a key effector in gene regulation during development, differentiation, and carcinogenesis, and it represents a promising target for therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yujiang Shi, Fei Lan, Caitlin Matson, et al. 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