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Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance

ABSTRACT: Lysine-specific demethylase 1 (LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here, we show that LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a LSD1 binding site (LBAL) downstream of Atrophin1 (ATN1). Surprisingly, tranylcypromine (LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ATN1 repression and NPC differentiation. Knockdown of LSD1 and ATN1 phenocopied each other in inducing NPC premature differentiation and depletion which could be rescued by ATN1 overexpression, suggesting that LSD1 controls NPC differentiation via regulation of ATN1 methylation status and expression. The involvement of LSD1 in ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, tranylcypromine, in the prevention and/or treatment of ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE62770 | GEO | 2015/04/29

SECONDARY ACCESSION(S): PRJNA265087

REPOSITORIES: GEO

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Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance

Project description:Lysine-specific demethylase 1 (LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here, we show that LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a LSD1 binding site (LBAL) downstream of Atrophin1 (ATN1). Surprisingly, tranylcypromine (LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ATN1 repression and NPC differentiation. Knockdown of LSD1 and ATN1 phenocopied each other in inducing NPC premature differentiation and depletion which could be rescued by ATN1 overexpression, suggesting that LSD1 controls NPC differentiation via regulation of ATN1 methylation status and expression. The involvement of LSD1 in ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, tranylcypromine, in the prevention and/or treatment of ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy. Examination of LSD1 binding sites in neuronal progenitor cells.

2015-04-29 | E-GEOD-62770 | biostudies-arrayexpress

The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells (ChIP-Seq data)

2012-03-29 | GSE36346 | GEO

Differentiating 3T3-L1 adipocytes, introduced with siRNA against aof2 and rfk genes, or treated with tranylcypromine

Project description:Adipogenic differentiation and metabolic adaptation are initiated through transcriptional and epigenetic reprogramming. In particular, dynamic changes in histone modifications may play central roles in the rearrangement of gene expression patterns. LSD1 (KDM1) protein, encoded by aof2 gene, is a histone demethylase, which is involved in transcriptional regulation. Since the enzymatic activity of LSD1 is FAD (flavin adenine dinucleotide)-dependent, its effects on gene expression may be influenced by FAD availability. To address the importance of histone demethylation in adipogenic differentiation and function, we performed cDNA microarray in LSD1-deficient 3T3-L1 cells as well as in the cells treated with LSD1 inhibitor tranylcypromine (TC). FAD-synthesizing enyme, riboflavin kinase (RFK) -deficient cells were also subjected to the microarray analysis.

2012-04-05 | GSE18598 | GEO

The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells (expression data)

Project description:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the genetic program regulated by KDM1A in murine MLL-AF9 AML cells enriched for LSCs, we compared the transcriptome of KIT+Gr1+ control and Kdm1a KD cells using exon arrays soon after initiation of KD. At this time, there was no immunophenotypic evidence of differentiation in Kdm1a KD cells. Exonic expression values were condensed into gene-level expression summaries, which represent the mean expression value of the probe sets targeting the length of a given protein coding gene. Three separate samples from two different animals were used. Kdm1a KD samples were compared with control samples. Total six arrays.

2012-03-28 | E-GEOD-36347 | biostudies-arrayexpress

Differentiating 3T3-L1 adipocytes, introduced with siRNA against aof2 and rfk genes, or treated with tranylcypromine

2012-04-04 | E-GEOD-18598 | biostudies-arrayexpress

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

Project description:The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis.

2020-05-26 | PXD012954 | Pride

The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells (ChIP-Seq data)

Project description:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the effects of Kdm1a KD on histone modifications, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) in control and Kdm1a KD MLL-AF9 AML cells for dimethyl-H3K4 and dimethyl-H3K9, as well as for trimethyl-H3K4 and trimethyl-H3K9. Dimethyl-H3K4 and dimethyl-H3K9 are targeted for demethylation by KDM1A. For each of these histone modifications, we compared the mean ChIP-Seq signal across and around protein coding genes bound by the MLL-AF9 oncoprotein (Bernt et al., 2011) with the mean signal from genes not bound by MLL-AF9 expressed at high, middle or low levels.

2012-03-28 | E-GEOD-36346 | biostudies-arrayexpress

Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation (expression)

Project description:Transcription factors and chromatin modifiers play important roles in programming and reprogramming of cellular states during development. Much is known about the role of these regulators in gene activation, but relatively little is known about the critical process of enhancer silencing during differentiation. Here we show that the H3K4/K9 histone demethylase LSD1 plays an essential role in decommissioning enhancers during differentiation of embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes critical for control of ESC state. However, LSD1 is not essential for maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to fully differentiate and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At enhancers, LSD1 is a component of the NuRD complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program upon differentiation, which is essential for complete shutdown of the ESC gene expression program and the transition to new cell states. This represents the expression part of the study.

2012-01-03 | E-GEOD-27714 | biostudies-arrayexpress

Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation (ChIP-seq)

2012-01-03 | E-GEOD-27841 | biostudies-arrayexpress

Expression data of differentiated human erythroid cells with or without Tranylcypromine (TC) treatment

Project description:We found that LSD1 inhibition by a monoamine oxidase inhibitor, tranylcypromine (TC), could enhance fetal gamma globin expression. Global effects of TC on erythroid expession were conducted by HG-U219 array strips.

2013-02-16 | GSE42078 | GEO

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