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RLS-associated MEIS transcription factors control distinct processes in human neural stem cells [ChIP-Seq]

ABSTRACT: MEIS1 and MEIS2 encode highly conserved homeodomain transcription factors crucial for developmental processes in a wide range of tissues, including the brain. They can execute redundant functions when co-expressed in the same cell types, but their roles during early stages of neural differentiation have not been systematically compared. By separate knockout and overexpression of MEIS1 and MEIS2 in human neural stem cells, we find they control specific sets of target genes, associated with distinct biological processes. Integration of DNA binding sites with differential transcriptomics implicates MEIS1 to co-regulate gene expression by interaction with transcription factors of the SOX and FOX families. MEIS1 harbors the strongest risk factor for restless legs syndrome (RLS). Our data suggest that MEIS1 can directly regulate the RLS-associated genes NTNG1, MDGA1 and DACH1, constituting new approaches to study the elusive pathomechanism or RLS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271673 | GEO | 2024/12/03

REPOSITORIES: GEO

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RLS-associated MEIS transcription factors control distinct processes in human neural stem cells [RNA-Seq]

Project description:MEIS1 and MEIS2 encode highly conserved homeodomain transcription factors crucial for developmental processes in a wide range of tissues, including the brain. They can execute redundant functions when co-expressed in the same cell types, but their roles during early stages of neural differentiation have not been systematically compared. By separate knockout and overexpression of MEIS1 and MEIS2 in human neural stem cells, we find they control specific sets of target genes, associated with distinct biological processes. Integration of DNA binding sites with differential transcriptomics implicates MEIS1 to co-regulate gene expression by interaction with transcription factors of the SOX and FOX families. MEIS1 harbors the strongest risk factor for restless legs syndrome (RLS). Our data suggest that MEIS1 can directly regulate the RLS-associated genes NTNG1, MDGA1 and DACH1, constituting new approaches to study the elusive pathomechanism or RLS.

2024-12-03 | GSE271674 | GEO

Restless Legs Syndrome-associated variant in MEIS1 confers altered gene expression in embryonic ganglionic eminences

Project description:Genome-wide association studies (GWASs) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and the functional relevance have remained to be elucidated. The MEIS1 locus contains an exceptionally large number of highly conserved non-coding regions (HCNRs), which potentially function as cis-regulatory modules. We analyzed the HCNRs in the RLS-associated linkage disequilibrium (LD) block for allele-dependent enhancer activity in both zebrafish and mouse, comparing the protective and risk alleles of RLS-associated common variants. We found one enhancer, harboring the lead SNP rs12469063, which showed an allele-dependent reduction of reporter gene expression exclusively in the embryonic ganglionic eminences at developmental stage E12.5. Notably, the reporter activity overlapped with the endogenous telencephalic Meis1 expression domain, which co-localized with transcripts of all four validated RLS loci. Thus, the developing telencephalon represents the first neuroanatomic region implicated for RLS based on GWAS findings. Total RNA obtained from 2-3 male and female mice E12.5 (wildtype, heterzygote, homozygote) and 3-4 male heterozygote and wildtype mice (adult)

2014-01-29 | E-GEOD-44592 | biostudies-arrayexpress

Restless Legs Syndrome-associated variant in MEIS1 confers altered gene expression in embryonic ganglionic eminences

2014-01-29 | GSE44592 | GEO

Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [ChIP-seq]

Project description:Meis1 and Meis2 are highly similar homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Overexpression experiments have suggested an essential role for Meis factors in limb proximo-distal patterning; however, loss-of-function experiments supporting this notion have not been reported. Meis1 and Meis2 are coexpressed during limb development, first in the lateral plate mesoderm, before limb induction, and then they become restricted to a proximal domain of the growing limb bud. Here, we report that complete double conditional Meis1/2 inactivation in the lateral plate mesoderm leads to limb agenesis. Meis factors cooperate with Tbx factors in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles develop a complete PD set of limb skeletal elements, but show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior skeletal element specification reveals an early role of Meis factors in establishing the limb AP prepattern required for Shh activation at later stages. Our results uncover novel roles for Meis transcription factors in early limb development and identify their involvement in new molecular interaction networks that regulate organogenesis

2020-05-25 | GSE134034 | GEO

Control of limb initiation and antero-posterior patterning by cooperation between Meis and Tbx transcription factors [RNA-seq]

2021-03-29 | GSE134039 | GEO

Meis homeobox genes control cell competence within the eye-specified neuroepithelium (ChIP-seq)

Project description:Vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. Eye-specified neuroepithelium forms the optic cup in which spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ) possessing both neurogenic and non-neurogenic potential, and the optic disc (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind the regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence and guardians of spatial territories in the vertebrate eye.

2021-02-17 | E-MTAB-10112 | biostudies-arrayexpress

Meis homeobox genes control cell competence within the eye-specified neuroepithelium (RNA-seq)

2021-02-17 | E-MTAB-9143 | biostudies-arrayexpress

MEIS2 is a novel oncogenic partner in AML1-ETO positive AML [Affymetrix]

Project description:MEIS2 collaborates with AML1-ETO in inducing acute myeloid leukemia in a murine bone marrow transplantation model We compared Gene expression profile (GEP) of murine bone marrow cells transduced with GFP, AML1-ETO, MEIS2, and AML1-ETO/MEIS2. Data from MEIS1 and AML1-ETO/MEIS1 is also included. Mouse bone marrow cells were kept in culture for 48hrs after retroviral transduction. GFP positive cells were then sorted and cells were kept for further 24 hours in culture before microarray analysis.

2016-07-04 | E-GEOD-81174 | biostudies-arrayexpress

Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis and retinoic acid

Project description:Vertebrate axial skeletal patterning is controlled by coordinated collinear expression of Hox genes and axial level-dependent activity of Hox protein combinations. Transcription factors of the Meis family act as cofactors of Hox proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning have not been established. Similarly, retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however whether this role is related to Meis/Hox regulation or functions in axial patterning remains unknown. Here we study the role of Meis factors in axial skeleton formation and its relationship to the RA pathway by characterizing Meis1, Meis2 and Raldh2 mutant mice. We report that Meis and Raldh2 regulate each other in a positive feedback regulatory loop that controls axial skeletal identity. Meis elimination produces homeotic transformations similar to those found in Raldh2 and anterior-Hox mutants and disrupts the expression of Hox target genes without changing the transcriptional profiles of Hox complexes. We propose that Meis regulates vertebrate axial skeleton patterning by exclusively affecting Hox protein function, and that alterations in RA levels can produce homeotic transformations without altering Hox transcription through regulating Meis expression.

2020-12-22 | GSE146301 | GEO

Meis genes regulate RA/FGF signaling to control multiple steps of limb development

Project description:Vertebrate limbs develop by integrating signals that control patterning along three main orthogonal axes. Flank-produced retinoic acid (RA) is initially required for limb induction and establishment of the apical ectodermal ridge (AER), a distal signaling center that produces fibroblast growth factors (FGFs), which are essential for limb growth and distalization. Once the AER is established, RA:FGF antagonism determines the restricted expression of a set of genes that control limb proximodistal patterning. Essential for this antagonism is the activation by FGF of the RA-degrading enzyme CYP26B1 in the distal limb bud. In addition, sonic hedgehog produced from the zone of polarizing activity (ZPA) is essential for distal limb anteroposterior patterning and contributes to RA reduction by cooperating in CYP26B1 activation. Meis transcription factors are expressed in the proximal limb bud, are activated by RA and can regulate proximodistal limb development; however, the mechanisms underlying their activity remain unknown. Here we studied Meis function in the mouse limb bud through Meis2 conditional overexpression and elimination of Meis1 and Meis2. We found that Meis activity is first required for limb bud initiation and the proper establishment of the AER and ZPA signaling centers, and subsequently for the development of proximal limb structures. Functional genomic analyses reveal that Meis is an important conveyor of the RA:FGF antagonism through the regulation of components of the RA and FGF signaling pathways, including CYP26B1. In addition, Meis regulates a set of proximal limb genes controlling proximodistal patterning and differentiation. Our work reveals a regulatory module essential for limb patterning and potentially co-opted in other patterning processes involving RA:FGF antagonism.

2018-09-25 | GSE51374 | GEO

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