Lactobacillus fermentum CECT5716 Supplementation in Rats During Pregnancy and Lactation Impacts Maternal and Offspring Lipid Profile, Immune System and Microbiota

Probiotics have shown potential for their use in early life. This study aimed to investigate whether the administration of Lactobacillus fermentum CECT5716 during pregnancy and lactation periods impacts maternal and offspring plasma lipid profile, immune system and microbiota. Rats were supplemented with the probiotic during gestation and two weeks of lactation. After supplementation, although the microbiota composition was not affected, the probiotic strain was detected in all cecal contents of dams and in some of their pups. Dams showed reduced proportion of T cytotoxic cells in the mesenteric lymph nodes, modulation of intestinal cytokines (IL-10 and IL-12) and changes in plasma fatty acids (20:0, 22:0, 20:5 n-3, and 18:3 n-6). Pups showed changes in immunoglobulins (intestinal IgA and plasmatic IgG2a and IgG2c) and fatty acid profile (17:0, 22:0, and 18:2 n-6). Overall, Lactobacillus fermentum CECT5716 supplementation contributed to beneficially modulating the immune system of the mother and its offspring

Immunomodulatory effect and maternal transmission of a probiotic strain of Lactobacillus isolated from human milk

Podeu consultar el III Workshop anual INSA-UB complet a: http://hdl.handle.net/2445/118993Sessió 1. Resultats del Programa FRI-INS

In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development

Class IIa histone deacetylase (HDAC) subfamily members are tissue-specific gene repressors with crucial roles in development and differentiation processes. A prominent example is HDAC7, a class IIa HDAC that shows a lymphoid-specific expression pattern within the hematopoietic system. In this study, we explored its potential role in B cell development by generating a conditional knockout mouse model. Our study demonstrates for the first time that HDAC7 deletion dramatically blocks early B cell development and gives rise to a severe lymphopenia in peripheral organs, while also leading to pro-B cell lineage promiscuity. We find that HDAC7 represses myeloid and T lymphocyte genes in B cell progenitors through interaction with myocyte enhancer factor 2C (MEFC2). In B cell progenitors, HDAC7 is recruited to promoters and enhancers of target genes, and its absence leads to increased enrichment of histone active marks. Our results prove that HDAC7 is a bona fide transcriptional repressor essential for B cell development

Unveiling novel functions of the trascriptional repressor HDAC7 in B lymphocyte development

[eng] B lymphopoiesis is the result of several cell lineage choices and differentiation steps whose perturbation leads to B cell malignancies. Cellular transitions for B cell generation have been associated with gene activation and silencing by networks of B cell specific transcription factors (TFs) and dynamic changes in DNA methylation. How gene repression is established and which lineage-specific transcriptional repressors are involved during B cell lymphopoiesis is still not totally understood. The Cellular Differentiaion group had previously reported that the transcriptional repressor HDAC7 is highly expressed in B cell progenitors (pro-B cells) and B cell precursors (pre-B cells) but not in myeloid cells such as macrophages. Here, we have demonstrated that HDAC7 is essential for early B cell development and the acquisition of proper B cell identity. There is a block of pro-B to pre-B cell stages transition and a significant increase of cell death rate upon HDAC7 deletion in these populations. We found that HDAC7 represses myeloid and T lymphocyte genes in pro-B cells through specific interaction with the TF MEF2C. Chromatin immunoprecipitation (ChIP) experiments revealed that HDAC7 is recruited to the promoters and enhancers of lineage inappropriate genes in normal pro-B, leading to their transcriptional silencing. Notably, by using in vivo and in vitro experimental approaches, we found that HDAC7 represses Tet2 in pro-B. On one hand, microarray and RT-qPCR analysis showed that Tet2 expression is up-regulated in pro-B cells from HDAC7-deficient mice. On the other hand, we found that HDAC7 is down-regulated during the conversion of pre-B cells into macrophages and its exogenous expression blocks the up-regulation of Tet2. Similarly to the case of other lineage inappropriate lineage genes, HDAC7 is recruited to the promoter and enhancer of the Tet2 gene in pro-B cells and its absence leads to an increase and a decrease in active and repressive histone marks, respectively. Additionally, we observed that the absence of HDAC7 from pro-B cells results in a significant increase in the percentage of global 5-hydroxymethylation (5-hmC). To definitively prove the role of HDAC7 in 5-hmC, we performed a genome-wide experimental approach. hMeDIP- sequencing experiments revealed an increase in the enrichment of this epigenetic modification at many loci related to lineage inappropriate genes in the absence of HDAC7. Interestingly, we observed 5-hmC enrichment at retrotransposon elements (LINE-1) in HDAC7 deficient pro-B cells, suggesting a potential protector function of HDAC7 against chromatin instability and DNA damage. Additonal results revealed that 5-hmC enrichment at microRNAs and their expression was also regulated by HDAC7. Several miRNAs involved in normal and aberrant hematopoiesis changed their expression levels depending on the presence of HDAC7 in pro-B cells. Finally, we found that HDAC7 is expressed at very low levels in certain hematological malignancies, such as Burkitt lymphoma and B cell acute lymphoblastic leukemia (B-ALL) cell lines. In fact, induction of HDAC7 expression in these tumoral cells led to the activation of apoptotic processes, reducing significantly their viability, and to the reduction of oncogene c-MYC expression. Importantly, those effects were observed by interaction with the TF MEF2C and independently of the class I HDAC3 function. These results suggest an anti-oncogenic role for HDAC7 in some types of B cell malignancies. Altogether, our results demonstrate that HDAC7 is an essential transcriptional repressor during early B cell development that silences lineage or functionally inappropriate genes at multiple levels. It exerts its function by direct recruitment to target genes through specific TF, by regulating LINE-1 and miRNA expression and by controlling the expression levels of a critical epigenetic regulator such as TET2 demethylase enzyme.[cat] Les proteïnes de la família de desacetilases d’histones de classe IIa (HDACs per les seves sigles en anglès) són repressors transcripcionals amb expressió específica de teixit i juguen un paper essencial en processos de desenvolupament i diferenciació cel·lular. Dins del sistema hematopoètic, la HDAC de classe IIa HDAC7 s’expressa en cèl·lules B, T i NK. Dins del llinatge de les cèl·lules B, HDAC7 s’encarrega de reprimir l’expressió de gens d’altres tipus cel·lulars, com els macròfags i les cèl·lules T. Per tal de dur a terme aquest silenciament, HDAC7 és reclutada als promotors i regions reguladores més allunyades dels seus gens diana mitjançant la interacció amb el factor de transcripció MEF2C. Un dels gens reprimits per HDAC7 en els limfòcits B és l’enzim TET2, el qual s’encarrega de catalitzar l’hidroximetilació (5-hmC) de l’ADN, propiciant la subseqüent desmetilació i activació dels gens. Mitjançant la deleció d’ HDAC7 en cèl·lules B progenitores en un model de ratolí, vam observar un augment de l’expressió i l’activitat de TET2, el qual produïa un augment dels nivells d’hidroximetilació globals de l’ADN, d’hidroximetilació i expressió específica dels gens de llinatges alternatius, d’activitat dels retro-transposons LINE-1 i de l’expressió de microRNAs involucrats en el desenvolupament d’altres llinatges i en tumorogènesi. Pel que fa a la funció de HDAC7 en càncers hematològics, vam observar que aquesta proteïna presenta uns nivells d’expressió molt baixos en alguns tipus de leucèmia i limfoma. Curiosament, la inducció de l’expressió d’HDAC7 en cèl·lules d’aquestes patologies produïa la disminució d’expressió de l’oncogen c-Myc i l’activació de processos apoptòtics. En conjunt, els resultats obtinguts demostren que HDAC7 és un regulador crític i indispensable pel correcte desenvolupament dels limfòcits B i per al manteniment de la seva identitat cel·lular, essent la seva desregulació una causa potencial de transformació cel·lular maligna. Aquesta regulació la realitza a múltiples nivells, incloent el reclutament directe a regions reguladores dels seus gens diana, la modulació indirecte dels nivells de metilació de DNA i la influència sobre els nivells d’expressió de microRNAs. Els descobriments obtinguts amplien les perspectives funcionals de la família de desacetilases d’histones, com HDAC7, el context biològic de cada membre

Associations of breast milk microbiota, immune factors, and fatty acids in the rat mother-offspring pair

The present study aimed to analyze the rat breast milk profile of fatty acids (FA), immunoglobulins (Ig), microbiota, and their relationship, and to further assess their associations in the mother-offspring pair. Dams were monitored during the three weeks of gestation, allowed to deliver at term, and followed during two weeks of lactation. At the end of the study, milk was obtained from the dams for the analysis of fatty acids, microbiota composition, immunoglobulins, and cytokines. Moreover, the cecal content and plasma were obtained from both the dams and pups to study the cecal microbiota composition and the plasmatic levels of fatty acids, immunoglobulins, and cytokines. Rat breast milk lipid composition was ~65% saturated FA, ~15% monounsaturated FA, and ~20% polyunsaturated FA. Moreover, the proportions of IgM, IgG, and IgA were ~2%, ~88%, and ~10%, respectively. Breast milk was dominated by members of Proteobacteria, Firmicutes, and Bacteroidetes phyla. In addition, forty genera were shared between the milk and cecal content of dams and pups. The correlations performed between variables showed, for example, that all IgGs subtypes correlated between the three compartments, evidencing their association in the mothermilk-pup line. We established the profile of FA, Ig, and the microbiota composition of rat breast milk. Several correlations in these variables evidenced their association through the mother-milkpup line. Therefore, it would be interesting to perform dietary interventions during pregnancy and/or lactation that influence the quality of breast milk and have an impact on the offspring

Immunomodulatory effect and maternal transmission of a probiotic strain of Lactobacillus isolated from human milk

Podeu consultar el III Workshop anual INSA-UB complet a: http://hdl.handle.net/2445/118993Sessió 1. Resultats del Programa FRI-INS

In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development

Class IIa histone deacetylase (HDAC) subfamily members are tissue-specific gene repressors with crucial roles in development and differentiation processes. A prominent example is HDAC7, a class IIa HDAC that shows a lymphoid-specific expression pattern within the hematopoietic system. In this study, we explored its potential role in B cell development by generating a conditional knockout mouse model. Our study demonstrates for the first time that HDAC7 deletion dramatically blocks early B cell development and gives rise to a severe lymphopenia in peripheral organs, while also leading to pro-B cell lineage promiscuity. We find that HDAC7 represses myeloid and T lymphocyte genes in B cell progenitors through interaction with myocyte enhancer factor 2C (MEFC2). In B cell progenitors, HDAC7 is recruited to promoters and enhancers of target genes, and its absence leads to increased enrichment of histone active marks. Our results prove that HDAC7 is a bona fide transcriptional repressor essential for B cell development

In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development

Class IIa histone deacetylase (HDAC) subfamily members are tissue-specific gene repressors with crucial roles in development and differentiation processes. A prominent example is HDAC7, a class IIa HDAC that shows a lymphoid-specific expression pattern within the hematopoietic system. In this study, we explored its potential role in B cell development by generating a conditional knockout mouse model. Our study demonstrates for the first time that HDAC7 deletion dramatically blocks early B cell development and gives rise to a severe lymphopenia in peripheral organs, while also leading to pro-B cell lineage promiscuity. We find that HDAC7 represses myeloid and T lymphocyte genes in B cell progenitors through interaction with myocyte enhancer factor 2C (MEFC2). In B cell progenitors, HDAC7 is recruited to promoters and enhancers of target genes, and its absence leads to increased enrichment of histone active marks. Our results prove that HDAC7 is a bona fide transcriptional repressor essential for B cell development