Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice

Leinonen, Henri; Koivisto, Hennariikka; Lipponen, Henna-Riikka; Matilainen, Anna; Salo, Antti M.; Dimova, Elitsa Y.; Hämäläinen, Elina; Stavén, Saara; Miettinen, Pasi; Myllyharju, Johanna; Koivunen, Peppi; Tanila, Heikki

doi:10.1016/j.neuropharm.2019.04.023

Cited by 15 publications

(20 citation statements)

References 37 publications

(44 reference statements)

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“…Regarding the association rs62259947: YY1 → P4HTM, P4HTM has been related with neurological disorders and social behaviour [38,39]. It is involved in Ca 2+ signalling mediated by the hypoxia-inducible factor HIF1α altering astrocytes gliotransmission [38].…”

Section: Discussionmentioning

confidence: 99%

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Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Preprint

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Background: Major Depression is the leading cause of impairment worldwide. The understanding of its molecular underpinnings is key to identifying new potential biomarkers and drug targets to alleviate its burden in society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of Major Depression associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with Major Depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis using GTEx data and alteration of transcription factor binding sites with pattern matching approaches and chromatin accessibility data.Results: The fine-mapping of major depression genetic variants uncovered putative causally associated variants whose proximal genes were linked with Major Depression pathophysiology. Four genetic variants altering the expression of 5 genes were found by colocalization analysis, highlighting the role of SLC12A5, involved in chlorine homeostasis in neurons, and MYRF, related with central nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of the genomic variant rs62259947 in modulating the expression of P4HTM through the alteration of YY1 binding site, altogether regulating hypoxia response.Conclusions: The combination of GWAS signals, cis-eQTL, transcription factor binding site information and active regulatory regions in the chromatin, enabled the prioritization of putative causal genetic variants in Major Depression. Importantly, our pipeline can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, hypoxia has been associated with mental disorders in general and MD in particular [61-64]. In addition, P4HTM null mutation results in a reduction in fear and depression [39]. In turn, rs62259947 downregulates the expression of P4HTM and changes the binding a nity of YY1 in the Brain Cerebellar Hemisphere.…”

Section: Discussionmentioning

confidence: 99%

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Pérez-Granado

Piñero

Medina-Rivera

et al. 2022

Preprint

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“…Furthermore, P4H-TM also hydroxylated to a small extent HIF1α ODDD in which the HIF-P4H-targeted prolines were mutated to alanines. In addition, the behavioral phenotype of the P4H-TM KO mice is very different from any other HIF-P4H KO mice (20), and the symptoms of the patients with HIDEA syndrome have not been reported to be linked to HIF-P4H deficiency (21,22). P4H-TM contains a putative EF domain with calcium-binding EF-hand motifs not found in any other characterized 2OGDD superfamily enzyme.…”

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confidence: 84%

“…In mice, P4H-TM is involved in regulation of erythropoietin levels and erythrocytosis (19). P4h-tm −/− mice develop early-onset aging-associated retinal and renal dysfunction (18), and their behavioral phenotype is characterized by hyperactivity and a dramatic reduction of despair response (20).…”

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confidence: 99%

Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains

Myllykoski

Sutinen

Koski

et al. 2021

Journal of Biological Chemistry

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Edited by Joseph Jez Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a third P4H-the poorly characterized endoplasmic reticulum-localized transmembrane prolyl 4-hydroxylase (P4H-TM)-is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome, but how these variants might contribute to disease is unknown. Here, we explored this question in a structural and functional analysis of soluble human P4H-TM. The crystal structure revealed an EF domain with two Ca 2+-binding motifs inserted within the catalytic domain. A substrate-binding groove was formed between the EF domain and the conserved core of the catalytic domain. The proximity of the EF domain to the active site suggests that Ca 2+ binding is relevant to the catalytic activity. Functional analysis demonstrated that Ca 2+-binding affinity of P4H-TM is within the range of physiological Ca 2+ concentration in the endoplasmic reticulum. P4H-TM was found both as a monomer and a dimer in the solution, but the monomer-dimer equilibrium was not regulated by Ca 2+. The catalytic site contained bound Fe 2+ and N-oxalylglycine, which is an analogue of the cosubstrate 2-oxoglutarate. Comparison with homologous P4H structures complexed with peptide substrates showed that the substrateinteracting residues and the lid structure that folds over the substrate are conserved in P4H-TM, whereas the extensive loop structures that surround the substrate-binding groove, generating a negative surface potential, are different. Analysis of the structure suggests that the HIDEA variants cause loss of P4H-TM function. In conclusion, P4H-TM shares key structural elements with other P4Hs while having a unique EF domain. This article contains supporting information.

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“…Highest HIF-P4H-3 expression has been detected in the heart [15] and HIF-P4H-3 seems to be particularly strongly expressed in epithelial cells of various tissues [19]. P4H-TM expression has been detected in the brain, eye, heart, lung, skeletal muscle and kidney, and it seems to play specific roles in neuronal tissues, e.g., the retinal pigment epithelium and astrocytes [20,21]. In the brain, P4H-TM was particularly abundant in regions related to emotional and social behaviour, which is in accordance with decreased anxiety and behavioural despair and increased social behaviour of P4h-tm −/− mice [20].…”

Section: Introductionmentioning

confidence: 99%

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

Dengler

Sova

Salo

et al. 2021

IJMS

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The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in “physiological hypoxia” and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1−/−, Hif-p4h-2 hypomorph and Hif-p4h-3−/− mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.

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Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice

Cited by 15 publications

References 37 publications

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

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