PZP and PAI-2: Structurally-diverse, functionally similar pregnancy proteins?

Wyatt, Amy R.; Cater, Jordan H.; Ranson, Marie

doi:10.1016/j.biocel.2016.08.018

Cited by 27 publications

(35 citation statements)

References 36 publications

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“…For example, one of the top genes was PZP , pregnancy-zone protein gene, which had higher DNA methylation in the promoter and first exon region and lower gene expression in liver from males. PZP is known to inhibit proteinases and is upregulated in inflammatory conditions where it is believed to exert cellular-protective effects ( 52 ). Most plasma PZP is synthesized by the liver ( 53 ), and in agreement with our results, other studies have found higher serum levels of this protein in females ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

García-Calzón

Perfilyev

Mello

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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ContextEpigenetics may contribute to sex-specific differences in human liver metabolism.ObjectiveTo study the impact of sex on DNA methylation and gene expression in human liver.Design/SettingCross-sectional, Kuopio Obesity Surgery Study.Participants/InterventionWe analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)–cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants.ResultsFemales displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles.ConclusionsHuman liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

García-Calzón

Perfilyev

Mello

et al. 2018

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…The expression in this cluster of Tph1 is consistent with a recent report that the majority of enterochromaffin cells in the mouse small intestine co-produce other gut hormones including PYY, GLP-1, and CCK [21] . The strongest marker of Cl3 was Pzp , an alpha2 macroglobulin of uncertain function [22] . Cl3 appeared distinct to the upper small intestine, as mRNA for Pzp was low in PPG-cells purified from the lower small intestine; a trend for higher expression in PPG-cells from the proximal compared to the distal intestine was also observed for another CL3 enriched gene Tph1 ( Figure S7 ), although this does not exclude that a relatively smaller sub-population of Pzp and/or Tph1 co-expressing cells is present in the more distal PPG population.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine

Glass

Calero-Nieto

Jawaid

et al. 2017

Molecular Metabolism

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ObjectivesTo identify sub-populations of intestinal preproglucagon-expressing (PPG) cells producing Glucagon-like Peptide-1, and their associated expression profiles of sensory receptors, thereby enabling the discovery of therapeutic strategies that target these cell populations for the treatment of diabetes and obesity.MethodsWe performed single cell RNA sequencing of PPG-cells purified by flow cytometry from the upper small intestine of 3 GLU-Venus mice. Cells from 2 mice were sequenced at low depth, and from the third mouse at high depth. High quality sequencing data from 234 PPG-cells were used to identify clusters by tSNE analysis. qPCR was performed to compare the longitudinal and crypt/villus locations of cluster-specific genes. Immunofluorescence and mass spectrometry were used to confirm protein expression.ResultsPPG-cells formed 3 major clusters: a group with typical characteristics of classical L-cells, including high expression of Gcg and Pyy (comprising 51% of all PPG-cells); a cell type overlapping with Gip-expressing K-cells (14%); and a unique cluster expressing Tph1 and Pzp that was predominantly located in proximal small intestine villi and co-produced 5-HT (35%). Expression of G-protein coupled receptors differed between clusters, suggesting the cell types are differentially regulated and would be differentially targetable.ConclusionsOur findings support the emerging concept that many enteroendocrine cell populations are highly overlapping, with individual cells producing a range of peptides previously assigned to distinct cell types. Different receptor expression profiles across the clusters highlight potential drug targets to increase gut hormone secretion for the treatment of diabetes and obesity.

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“…More recently, SERPINB2 has been shown to reach to extracellular space. For example, SERPINB2 is secreted by endothelial cells in response to inflammatory stimulus, can move into extracellular space on surface of microparticles originating from cancer cells and is known to be present in the blood plasma during pregnancy . The function of extracellular SERPINB2 is to inhibit the extracellular protease urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), which convert plasminogen to plasmin, a protease involved in extracellular matrix degradation and cell migration, macrophage invasion and adhesion, fibrinolysis and mediation of inflammation and tissue remodelling …”

Section: Introductionmentioning

confidence: 99%

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

Vaher

Kivihall

Runnel

et al. 2019

Experimental Dermatology

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Psoriasis is a chronic inflammatory skin disease with numerous involved factors. miR‐146a and miR‐146b (miR‐146a/b) are anti‐inflammatory miRNAs that are increased in psoriatic skin. SERPINB2 has been shown to be upregulated in the inflammation and infections. Here we aimed to study the relationship between miR‐146a/b and SERPINB2 and to delineate the role of SERPINB2 in association of plaque psoriasis. We report increased SERPINB2 expression in the skin of psoriasis patients, which was in a positive relationship with psoriasis severity and in a negative relationship with miR‐146a/b in psoriatic lesions. In cultured keratinocytes, both cellular and secreted SERPINB2 levels were strongly induced in response to IFN‐γ and TNF‐α. Interestingly, SERPINB2 mRNA was downregulated by IL‐17A and the combination of TNF‐α and IL‐17A at time points when miR‐146a was increased. The predicted binding site for miR‐146a/b in 3’ untranslated region of SERPINB2 revealed no activity in luciferase assay, while siRNA silencing of miR‐146a/b direct targets IRAK1 and CARD10 resulted in reduced expression of SERPINB2, suggesting that miR‐146a/b indirectly control SERPINB2 expression in the skin. The siRNA silencing of SERPINB2 increased the expression of IL‐8, CXCL5 and CCL5 and migration of neutrophils revealing its anti‐inflammatory role in keratinocytes. Our data together suggest that SERPINB2 and miR‐146a/b are part of disease‐related network of molecules that are coordinately regulated and act in controlling the inflammatory responses in psoriatic skin.

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PZP and PAI-2: Structurally-diverse, functionally similar pregnancy proteins?

Cited by 27 publications

References 36 publications

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels

Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine

SERPINB2 and miR‐146a/b are coordinately regulated and act in the suppression of psoriasis‐associated inflammatory responses in keratinocytes

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