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Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

ABSTRACT: To understand the effect of SET protein accumulation on genomic function we used different accumulating models, cells and in vivo, that we analyzed with different techinques up to the single level. SET accumulation is known to be caused by the accumulation of its direct interactor SETBP1, when mutated, the causative gene of Schinzel Giedion syndrome. SET has been shown to be able to interfere with histones acetylation, thus we wanted to investigated the functional effect on the genome function and cell fate commitment.

ORGANISM(S): Mus musculus Danio rerio Homo sapiens

PROVIDER: GSE212252 | GEO | 2022/09/12

REPOSITORIES: GEO

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Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition.

Project description:Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that a condition in which SET is accumulated, the severe Schinzel-Giedion Syndrome (SGS), is characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of SGS and possibly other the SET-related disorders in humans.

| S-EPMC10239470 | biostudies-literature

Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

Project description:Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

| PRJNA874714 | ENA

Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Project description:Mutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways.

2021-05-18 | GSE158379 | GEO

Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.

Project description:Background: SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. Methods: Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. Results: The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. Limitations: The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. Conclusions: We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

2024-10-02 | GSE262710 | GEO

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Project description:Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs—most strongly upregulating Myc and Myc target genes. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.

2022-05-11 | GSE189502 | GEO

Characterization of SETBP1-deficient hESCs in vitro differentiated towards cortical neuroprogenitors and neurons

Project description:Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite SETBP1 association with neurodevelopmental disorders, little is known about its possible role during brain development. Using CRISPR/CAS9 genome editing technology, we generated SETBP1-deficient hESC lines and found that the derived cortical neural progenitors (NPCs) exhibit protracted proliferation and distorted layer-specific neuronal differentiation with overall decrease in neurogenesis. We analysed by genome wide transcriptome profiling the DEG and dysregulated pathways related to SETBP1-deficiency.

2023-03-01 | GSE180185 | GEO

Molecular signature of Schinzel-Giedion syndrome in human neural progenitors

Project description:Schinzel-Giedion syndrome (SGS) is a developmental syndrome, due to the accumulation of SETBP1 protein, which is fatal in early infancy. SGS has a multi-organ involvement with severe and persistent intellectual and physical problems. We produced a human SGS model that outlines disease-relevant phenotypes using patient-derived induced pluripotent stem cells and isogenic controls. Whole transcriptome profiling describes cancer-like alterations in SGS neural progenitors including deregulation of oncogenes and suppressors and enhanced proliferation. These findings demonstrated how SGS post-natal pathological traits mayhave developmental origin in the failure of controlling cell identity and homeostasis due to SETBP1 protein accumulation.

2021-06-03 | GSE150810 | GEO

Transcriptional regulation by SETBP1 and SETBP1(D/N) in mouse hematopoietic stem and progenitor cells

Project description:Global gene expression changes induced by Setbp1 and Setbp1(D/N) in purified mouse hematopoietic stem and progenitor cells were characterized by RNA-seq analysis; ChIP-seq studies to identify cooperation between SETBP1/SETBP1(D/N) and MLL1 in regulating gene transcription in hematopoietic stem and progenitor cells.

2021-12-17 | GSE167301 | GEO

SETBP1-WT and SETBP1-G870S transcriptional profiles [RNA-Seq]

Project description:RNA-Seq experiments on SETBP1-G870S and Empty cells was performed in order to assess if the presence of mutated SETBP1 may induce differential RNA expression.

2017-09-01 | GSE86333 | GEO

Becoming a balanced, proficient bilingual: Predictions from age of acquisition & genetic background.

Project description:Genetic variants related to dopamine functioning (e.g., the ANKK1/TaqIa polymorphism within the DRD2 gene and the Val158Met polymorphism within the COMT gene) have previously been shown to predict cognitive flexibility and learning (e.g., Colzato et al., 2010; Stelzel et al., 2010). Additionally, researchers have found that these genetic variants may also predict second language learning (Mamiya et al., 2016), although this relationship may change across the lifespan (Sugiura et al., 2011). The current study examined the role of the ANKK1/TaqIa and Val158Met polymorphisms along with age of second language acquisition (AoA) in order to predict levels of bilingual proficiency in Spanish-English bilinguals. Results indicated a three-way interaction such that the relationship between the genetic variants and bilingual proficiency depended on AoA. At earlier AoAs, having the genetic variant associated with higher levels of subcortical dopamine (A1+) predicted the highest levels of bilingual proficiency. At later AoAs, individuals with the genetic variant associated with cortical dopamine levels that are balanced between stability and flexibility (Val/Met) predicted the highest levels of bilingual proficiency. These results fit with theories about the development of language as a subcortical process early in life and as a cortical process later in life (Hernandez & Li, 2007), as well as the importance of both stability and flexibility in bilingual language development (Green & Abutalebi, 2013). Finally, this study raises questions about the direction of causality between bilingualism and cognitive control, which is central to the debate over the "bilingual advantage."

| S-EPMC6054315 | biostudies-literature

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