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The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [ChIP-Seq]

ABSTRACT: During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58258 | GEO | 2015/06/05

SECONDARY ACCESSION(S): PRJNA251753

REPOSITORIES: GEO

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The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

2015-06-05 | GSE63097 | GEO

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development. In order to find some LSD1+8a regulated genes at differentiated SH-SY5Y cell lines, we infected SH-SY5Y with control or LSD1+8a shRNA, then induced differentiation with RA and BDNF, (Retinoic acid (RA) (Sigma) was added at a final concentration of 10 μM the next day after plating. After 4 days, the cells were washed three times with PBS and incubated with 50 ng/mL of Brain Derived Neural Factor (BDNF) (Millipore) in serum-free medium for 3 days), we extracted RNA from BDNF induced SH-SY5Y cells for expression analysis.Duplicates were included for Affymetrix Human transcriptome version 2 array.

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Alternative splicing of LSD1+8a is mediated by SRRM4 in Neuroendocrine Prostate Cancer

Project description:Neuroendocrine prostate cancer (NEPC) is the most virulent subtype. Currently, there is an urgent need to identify new biomarkers and therapeutic targets in NEPC. The splicing factor SRRM4 was previously demonstrated to be highly expressed in NEPC, to promote expression of genes linked to neuroendocrine differentiation and cancer progression, and to promote alternate splicing of genes, including REST. One of REST’s binding protein is lysine specific demethylase 1 (LSD1). Importantly, a transcript variant of LSD1 called LSD1+8a is expressed in neuronal tissues and promotes neuronal gene expression. However, there was no information about LSD1+8a’s importance in prostate cancer. Using adenocarcinoma and NEPC patient-derived xenografts and clinical specimens, we determined that LSD1+8a was expressed exclusively in NEPC. Furthermore, LSD1+8a expression was significantly correlated with elevated mRNA expression of SRRM4. Using SRRM4-overexpressing prostate cancer cell lines, we determined that alternative splicing of LSD1+8a is directly mediated by SRRM4 and that LSD1+8a and SRRM4 co-regulate a unique program of cancer-promoting genes that is not regulated by canonical LSD1. Our findings demonstrate that measurement of LSD1+8a expression is a promising NEPC biomarker and suggest that targeting LSD1+8a in NEPC may be a useful strategy to block expression of genes linked to cancer progression.

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Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.

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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.

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Histone Demethylase Lsd1 is Required to Repress Hematopoietic Stem and Progenitor Cell Signatures During Blood Cell Maturation

Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on LysM-bM-^@M-^I4 or LysM-bM-^@M-^I9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. To identify direct target genes of Lsd1 in myeloid cells we mapped global occupancy of Lsd1 in 32D granuolocytic progenitor cells and compared H3K4me1/me2/me3 and H3K27ac histone modifications in Lsd1fl/fl (wild type) vs. Lsd1fl/f Mx1Cre (knockout) Gr1dim Mac1 granuolocytic progenitor cells.

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Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

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Genome-wide maps of chromatin state in pre-osteoblastic and lineage-committed cells.

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LSD1 Conditional Knockout Mice Have an Increased Bone Mass Due to Increased IFN-B Gene Expression

Project description:Osteoclasts are large multinucleated cells that degrade bone mineral and extracellular matrix. Investigating the mechanisms by which osteoclast differentiation is epigenetically regulated is a key to understanding the pathogenesis of skeletal related diseases such as periodontitis and osteoporosis. Lysine specific demethylase 1 (LSD1/KDM1A) is a member of the histone demethylase family that regulates gene expression via the removal of mono- and dimethyl groups from H3K4 and H3K9. Prior to our study, little was known about the effect of LSD1 on skeletal development and osteoclast differentiation. Here we show conditional deletion of LSD1 in the myeloid lineage or macrophage/osteoclast precursors results in a decrease in osteoclast differentiation and activity. Our bulk RNA-SEQ data suggests that osteoclast differentiation is inhibited in LSD1cKO mice due to an increase in expression of IFN-b target genes. Lastly, we demonstrate that LSD1 can form a complex with CoREST, HDAC1 and HDAC2 suggesting a mechanism by which the combination of methylation and acetylation of histone residues regulates osteoclast gene expression.

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