Cell type specification relies on the capacity of undifferentiated cells to properly respond to specific differentiation-inducing signals. Using genomic approaches along with loss- and ...gain-of-function genetic models, we identified OCT4-dependent mechanisms that provide embryonic stem cells with the means to customize their response to external cues. OCT4 binds a large set of low-accessible genomic regions. At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR or β-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors. As a proof of concept, we demonstrate that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells. Our results uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses.
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•OCT4 occupies differentiation-related and low-accessible genomic regions in ESCs•OCT4 positively controls the level of RARγ•Loss of OCT4 causes dysregulation of tissue-specific RA and WNT/β-catenin response•Overexpression of OCT4 is sufficient to reprogram a cell type-specific signal response
Simandi et al. demonstrate that, beyond maintaining pluripotency, OCT4 plays a role in integrating responses to signals differentiating embryonic stem cells. OCT4 primes a large set of low-accessible genomic regions and is required for their proper activation upon retinoic acid or WNT signal exposure.
The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic ...immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo1,2-apyrazine, imidazo1,5-aquinoxaline, and pyrazolo1,5-aquinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo1,5-aquinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.
Postpartum depression (PPD) appears at two peak periods: early-onset prior to 2 months after delivery and late-onset (2 months after delivery and beyond). The aim of our study is to evaluate the ...different genetic factors associated with early- and late-onset PPD. With the French multicenter interaction of gene and environment of depression during postpartum (IGEDEPP) cohort, we conducted a genome-wide association study (GWAS) on 234 women with early-onset PPD and 223 women with late-onset PPD, as well as 1,204 controls with no history of lifetime depression. We performed post-GWAS analyses: functional mapping and annotation of GWAS results using MAGMA thanks to Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA), expression quantitative trait loci (QTL) analyses, mapping using data from the PsychENCODE and GTEx, and polygenic risk score (PRS) analysis based on published GWAS. We found two new significant candidate loci for early-onset PPD, rs6436132 in
PTPRN
gene on chromosome 2 and rs184644645 in
RAD18
on chromosome 14, respectively, and one region of interest with five significant associated SNPs in chromosome 20 for late-onset PPD. Variant rs6436132 is the most significant associated with early-onset PPD, and it is a QTL that significantly modifies the expression and splicing of the
PTPRN
gene in different brain tissues. We also found an enrichment of uterus tissue in the early expression of PPD genes. PRS analysis showed a genetic overlap between both early and late-onset PPD and major depressive disorder, but only early-onset PPD overlaps with bipolar disorder. Our study presents two GWAS separately, highlighting two candidate loci for early-onset PPD and one different region of interest for late-onset PPD. These results have important consequences in our understanding of these disorders, especially since our data reinforce the hormonal pathophysiological hypotheses for early-onset PPD.
Although recent Genome‐Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome‐wide search for low‐frequency variants that affect the ...risk of venous thromboembolism (VTE). We conducted a meta‐analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene‐based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency MAF ~0.08%). We confirmed associations with previously identified VTE loci, including ABO,
F5,
F11, and
FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene‐based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low‐frequency and rare variants associated with VTE risk.
Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest ...familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome‐wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population‐based case‐control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray‐500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid‐stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.
What's new?
Differentiated thyroid carcinoma (DTC) has a strong genetic component, and Pacific Islanders have a particularly high incidence of the disease. Here, the authors conducted a genome‐wide association study (GWAS) in a mixed population including individuals of European and Pacific Islander ancestry. The study drew from the EPITHYR consortium, a collection of 2000 DTC cases and age‐matched controls. The analysis confirmed 5 previously known susceptibility loci and identified 2 new ones. Three of these loci were more prevalent among Pacific Islanders. More studies are needed to fully account for the rate of DTC in that population.
Host genetic factors contribute to the variability of malaria phenotypes and can allow a better understanding of mechanisms involved in susceptibility and/or resistance to
infection outcomes. Several ...genetic polymorphisms were reported to be prevalent among populations living in tropical malaria-endemic regions and induce protection against malaria. The present study aims to investigate the prevalence of
and
deficiencies polymorphisms among Senegalese populations and their associations with the risk for severe
malaria occurrence.
We performed a retrospective study with 437 samples, 323 patients recruited in hospitals located in three different endemic areas where malaria episodes were confirmed and 114 free malaria controls. The patients enrolled were classified into two groups: severe malaria (SM) (153 patients) and uncomplicated malaria (UM) (170 patients). PCR and DNA sequencing assessed host genetic polymorphisms in
and
. Using a multivariate regression and additive model, estimates of the impact of human
and
polymorphisms on malaria incidence were performed.
Six frequent SNPs with minor allele frequencies (MAF) > 3% were detected in the
gene (rs7946748, rs7480526, rs10768683, rs35209591, HbS (rs334) and rs713040) and two in the G6PD gene (rs762515 and rs1050828 (
-202 G > A). Analysis of selected HbS polymorphism showed significant association with protective effect against severe malaria with a significant
= 0.033 (OR 0.38, 95% CI 0.16-0.91) for SM
UM comparison. Surprisingly, our study did not identify the protective effect of variant HbC polymorphism against severe malaria. Finally, we found some of the polymorphisms, like HbS (rs334), are associated with age and biological parameters like eosinophils, basophils, lymphocytes etc.
Our data report
and
polymorphisms in the Senegalese population and their correlation with severe/mild malaria and outcome. The
and
deficiencies are widespread in West Africa endemic malaria regions such as The Gambia, Mali, and Burkina Faso. The study shows the critical role of genetic factors in malaria outcomes. Indeed, genetic markers could be good tools for malaria endemicity prognosis.
13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand ...the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence‐level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss‐of‐function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss‐of‐function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented. However, knowledge about specific microbiome structures in the ...human lung associated with CT defined abnormalities is limited.
Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons.
We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002). Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects. No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA. Co-occurrence analysis suggests the presence of networks of co-occurring bacteria. Four communities of positively correlated bacteria were revealed. The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype.
Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells. This might result in a changed interplay with the host immune system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogenous cellular processes. With a diversity of risk factors, liver cancer is an ideal model to ...study these interactions. Here, we analyze the whole genomes of 44 new and 264 published liver cancers and we identify 10 mutational and 6 structural rearrangement signatures showing distinct relationships with environmental exposures, replication, transcription, and driver genes. The liver cancer-specific signature 16, associated with alcohol, displays a unique feature of transcription-coupled damage and is the main source of CTNNB1 mutations. Flood of insertions/deletions (indels) are identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture reveals mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin B1 signature in African migrants. Finally, chromosome duplications occur late and may represent rate-limiting events in tumorigenesis. These findings shed new light on the natural history of liver cancers.
De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these ...reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C‐terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data‐sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.
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