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Opposing roles for the lncRNA Haunt and its genomic locus in regulating HOXA gene activation during embryonic stem cell differentiation

ABSTRACT: Long noncoding RNAs (lncRNAs) have been implicated in controlling various aspects of embryonic stem cell (ESC) biology, although the functions of specific lncRNAs, and the molecular mechanisms through which they act, remain unclear. Here, we demonstrate discrete and opposing roles for the lncRNA transcript Haunt and its genomic locus in regulating the HOXA gene cluster during ESC differentiation. Reducing or enhancing Haunt expression, with minimal disruption of the Haunt locus, led to up- or down-regulation of HOXA genes, respectively. In contrast, increasingly large genomic deletions within the Haunt locus attenuated HOXA activation. The Haunt DNA locus contains potential enhancers of HOXA activation, whereas Haunt RNA acts to prevent aberrant HOXA expression. This work reveals a multi-faceted model of lncRNA-mediated transcriptional regulation of the HOXA cluster, with distinct roles for a lncRNA transcript and its genomic locus, while illustrating the power of rapid CRISPR/Cas9-based genome editing for assigning lncRNA functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE58514 | GEO | 2015/04/20

SECONDARY ACCESSION(S): PRJNA252812

REPOSITORIES: GEO

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Opposing roles for the lncRNA Haunt and its genomic locus in regulating HOXA gene activation during embryonic stem cell differentiation

Project description:Long noncoding RNAs (lncRNAs) have been implicated in controlling various aspects of embryonic stem cell (ESC) biology, although the functions of specific lncRNAs, and the molecular mechanisms through which they act, remain unclear. Here, we demonstrate discrete and opposing roles for the lncRNA transcript Haunt and its genomic locus in regulating the HOXA gene cluster during ESC differentiation. Reducing or enhancing Haunt expression, with minimal disruption of the Haunt locus, led to up- or down-regulation of HOXA genes, respectively. In contrast, increasingly large genomic deletions within the Haunt locus attenuated HOXA activation. The Haunt DNA locus contains potential enhancers of HOXA activation, whereas Haunt RNA acts to prevent aberrant HOXA expression. This work reveals a multi-faceted model of lncRNA-mediated transcriptional regulation of the HOXA cluster, with distinct roles for a lncRNA transcript and its genomic locus, while illustrating the power of rapid CRISPR/Cas9-based genome editing for assigning lncRNA functions. All RNA-seq(s) were designed to reveal the differentially expressed genes among different stages of ESCs differentiation, or differentially expressed genes between wild-type or Haunt or HOXA mutant cells during RA-induced differentiation. All ChIRP-Seq were used to reveal the DNA or RNA targets of Haunt before or after RA treatment.

2015-04-20 | E-GEOD-58514 | biostudies-arrayexpress

Deletion of the Hoxa Cluster in MLL-AF9 Is Incompatible with Leukemia Maintenance: RNAseq-based Quantitative Analysis of Wild Type and Hoxa-del Transcriptomes

Project description:High HOXA expression correlates with poor clinical outcome in AML, particularly those harboring MLL rearrangements (MLLr). The necessity of the HOXA cluster for the maintenance of MLLr-leukemia has not been elucidated. Primary leukemias were generated by transduction of MLL-AF9 (MA9) into hematopoietic stem and progenitor cells from compound Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation, colony formation and repopulating ability in transplanted mice in which surviving leukemic cells retained at least one copy of the Hoxa cluster (Hoxa-del). Comparative RNA-seq analysis of leukemic MA9-Hoxa-wild type (WT) and MA9-Hoxa-del cells identified a unique gene signature.

2021-04-16 | GSE113200 | GEO

A CTCF binding element regulates RA-induced early ESCs differentiation through orchestrating long-range chromatin interactions between its adjacent enhancers and HoxA

Project description:Proper Homeobox A (HoxA) cluster genes expression is essential for embryonic stem cells (ESCs) differentiation and individual development. However, the mechanisms controlling the precise spatiotemporal expression of HoxA cluster genes during early ESCs differentiation remain largely unknown. Here, we find a CTCF binding element (CBE+47kb) closest to the 3'-end of HoxA locus within a topologically associated domains (TAD) in ESCs. CRISPR-Cas9 mediated the CBE+47kb knockout significantly promotes expression of HoxA cluster genes and early ESCs differentiation induced by RA compared with wild type cells. In mechanism, we found that there was a significant differently long-range chromatin interactions between its adjacent enhancers and HoxA in CBE+47kb knockout cells through chromosome conformation capture assay (Capture-C), indicating that CBE+47kb can precisely organize interactions between its adjacent enhancers and HoxA chromatins. Furthermore, we also showed that its adjacent enhancers deletion shows significantly synthetic inhibition effect on HoxA genes expression, suggesting that these enhancers are required for RA-induced HoxA genes expression. Our study reveals that a new functional CBE+47 can regulate HoxA genes expression through orchestrating long-range chromatin interactions between its adjacent enhancers and HoxA, thus maintaining RA-induced early ESCs proper differentiation.

2020-07-16 | GSE154495 | GEO

Highly conserved and cis-acting lncRNAs produced from paralogous regions in the center of HOXA and HOXB clusters in the endoderm lineage

Project description:Long noncoding RNAs (lncRNAs) have been shown to play important roles in gene regulatory networks acting in early development. There has been rapid turnover of lncRNA loci during vertebrate evolution, with few human lncRNAs conserved beyond mammals. The sequences of these rare deeply conserved lncRNAs are typically not similar to each other. Here, we characterize HOXA-AS3 and HOXB-AS3, lncRNAs produced from the central regions of the HOXA and HOXB clusters. Sequence-similar orthologs of both lncRNAs are found in multiple vertebrate species and there is evident sequence similarity between their promoters, suggesting that the production of these lncRNAs predates the duplication of the HOX clusters at the root of the vertebrate lineage. This conservation extends to similar expression patterns of the two lncRNAs, in particular in cells transiently arising during early development or in the adult colon. Functionally, the RNA products of HOXA-AS3 and HOXB-AS3 regulate the expression of their overlapping HOX5–7 genes both in HT-29 cells and during differentiation of human embryonic stem cells. Beyond production of paralogous protein-coding and microRNA genes, the regulatory program in the HOX clusters therefore also relies on paralogous lncRNAs acting in restricted spatial and temporal windows of embryonic development and cell differentiation.

2021-03-09 | GSE168444 | GEO

Dynamic lncRNA expression pattern during ESC-derived cardiac differentiation

Project description:Long noncoding RNAs (lncRNAs) have emerged as crucial regulators of gene expression during embryonic stem cell (ESC) self-renewal and differentiation. Here, we systemically analyzed the differentially regulated lncRNAs during ESC-derived cardiomyocyte (CM) differentiation. We established a perspicuous profile of lncRNA expression at four critical developmental stages and found that the differentially expressed lncRNAs were grouped into six distinct clusters. The cluster with specific expression in ESC enriches the largest number of lncRNAs. Investigation of lncRNA-protein interaction network revealed that they are not only controlled by classic key transcription factors, but also modulated by epigenetic and epitranscriptomic factors including N6-methyladenosine (m6A) effector machineries.

2022-03-01 | GSE197205 | GEO

Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster

Project description:This SuperSeries is composed of the following subset Series: GSE32362: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HumanMethylation450 BeadChip) GSE33129: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (Illumina HiSeq2000 sequencing) Refer to individual Series

2012-05-02 | E-GEOD-33130 | biostudies-arrayexpress

Enhancer architecture-dependent multilayered transcriptional regulation orchestrates RA signal-induced early differentiation of ESC

Project description:Signaling pathway driven target gene transcriptions are critical for fate determination of embryonic stem cells (ESC), but enhancer architecture-dependent transcriptional regulation remains largely unclear in this process. Here, we described a complex enhancer architecture-dependent multilayered transcriptional regulation that orchestrates retinoic acid (RA) signal-induced early differentiation of ESC. Specifically, we identified Hoxa1 and lncRNA Halr1 as the direct downstream target genes of RA signal. Chromosome conformation capture based screens show that increased enhancer interactions promoted by RA signal are essential for Hoxa1 and Halr1 expressions during early ESC differentiation. Furthermore, we find that HOXA1 promotes Halr1 expression through direct binding to enhancers; conversely, absence of Halr1 RNA enhances interaction between Hoxa1 chromatin and multiple enhancers, but weakens interaction with HoxA cluster internal chromatin, thereby promoting RA signal-induced Hoxa1 overactivation and early differentiation of ESC. These results indicate that Halr1 binds to chromatin not only acts as a brake to orchestrate interaction between enhancers and Hoxa1 chromatin, but also acts as a binder to maintain chromatin interaction within HoxA cluster. In summary, these findings reveal a complex multilayered transcriptional regulation involving the synergistic regulation of enhancer, transcription factor and lncRNA, and that increases our understanding of the intrinsic molecular mechanisms of RA signal-induced ESC differentiation.

2021-04-16 | GSE169058 | GEO

Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster (MeDIP-Seq)

Project description:Differentiation is accompanied by extensive epigenomic reprogramming, leading to the repression of stemness factors and the transcriptional maintenance of activated lineage-specific genes. Here we used the mammalian Hoxa cluster of developmental genes as a model system to follow changes in DNA modification patterns during retinoic acid induced differentiation. We found the inactive cluster to be marked by defined patterns of 5-methylcytosine (5mC). Upon the induction of differentiation, the active anterior part of the cluster became increasingly enriched in 5-hydroxymethylcytosine (5hmC), following closely the colinear activation pattern of the gene array, which was paralleled by the reduction of 5mC. Depletion of the 5hmC generating dioxygenase Tet2 impaired the maintenance of Hoxa activity and partially restored 5mC levels. Our results indicate that gene specific 5mC-5hmC conversion by Tet2 is crucial for the maintenance of active chromatin states at lineage-specific loci. Examination of 5-methylcytosine (MeDIP-seq) and 5-hydroxymethylcytosine (hMeDIP-seq) at the HOXA cluster in 2 different developmental stages of a pluripotent cancer cell line.

2012-05-02 | E-GEOD-33129 | biostudies-arrayexpress

Comprehensive Identification of Soybean Long Non-coding RNAs Reveals a Subset of Small Peptide-Coding Transcripts

Project description:Long non-coding RNAs (lncRNAs) are defined as non-protein-coding transcripts that are at least 200 nucleotides long. They are known to play pivotal roles in regulating gene expression, especially during stress responses in plants. We used a large collection of in-house transcriptome data from various soybean (Glycine max and Glycine soja) tissues treated under different conditions to perform a comprehensive identification of soybean lncRNAs. We also retrieved publicly available soybean transcriptome data that were of sufficient quality and sequencing depth to enrich our analysis. In total, RNA-seq data of 332 samples were used for this analysis. An integrated reference-based, de novo transcript assembly was developed that identified ~69,000 lncRNA gene loci. We showed that lncRNAs are distinct from both protein-coding transcripts and genomic background noise in terms of length, number of exons, transposable element composition, and sequence conservation level across legume species. The tissue-specific and time-specific transcriptional responses of the lncRNA genes under some stress conditions may suggest their biological relevance. The transcription start sites of lncRNA gene loci tend to be close to their nearest protein-coding genes, and they may be transcriptionally related to the protein-coding genes, particularly for antisense and intronic lncRNAs. A previously unreported subset of small peptide-coding transcripts was identified from these lncRNA loci via tandem mass spectrometry, which paved the way for investigating their functional roles. Our results also highlight the current inadequacy of the bioinformatic definition of lncRNA, which excludes those lncRNA gene loci with small open reading frames (ORFs) from being regarded as protein-coding.

2020-01-09 | PXD014553 | Pride

Expression and functions of long noncoding RNAs during human T helper cell differentiation

Project description:To improve our understanding of lncRNA expression in T cells, we used whole genome sequencing (RNA-seq) to identify lncRNAs expressed in human T cells and those selectively expressed in T cells differentiated under TH1, TH2, or TH17 polarizing conditions. The majority of these lineage-specific lncRNAs are co-expressed with lineage-specific protein-coding genes. These lncRNAs are predominantly intragenic with co-expressed protein-coding genes and are transcribed in sense and antisense orientations with approximately equal frequencies. Further, genes encoding TH lineage specific mRNAs are not randomly distributed across the genome but are highly enriched in the genome in genomic regions also containing genes encoding TH lineage-specific lncRNAs. Our analyses also identify a cluster of antisense lncRNAs transcribed from the RAD50 locus that are selectively expressed under TH2 polarizing conditions and co-expressed with IL4, IL5 and IL13 genes. Depletion of these lncRNAs via selective siRNA treatment demonstrates the critical requirement of these lncRNAs for expression of the TH2 cytokines, IL-4, IL-5 and IL-13. Collectively, our analyses identify new lncRNAs expressed in a TH lineage specific manner and identify a critical role for a cluster of lncRNAs for expression of genes encoding TH2 cytokines. Human peripheral blood mononuclear cells (PBMC) were cultured under TH1, TH2, and TH17 polarizing conditions. TH1, TH2, and TH17 primary and effector cultures were isolated and poly(A)+ and total RNA sequencing performed.

2015-04-23 | E-GEOD-66261 | biostudies-arrayexpress

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