Project description:The experiment aimed at determining the genes that are under the control of the Ikaros transcription factor in mouse splenic B1 and B2 B lymphocyte subsets. To this aim, we used Ikf/f R26-CreERT2+ (Cre+) or Ikf/f R26-CreERT2- (Cre-) mice, which correspond to mice with floxed null alleles for Ikzf1 (Heizmann et al., JEM 210:2823-32, 2013) that were crossed with the R26-CreERT2 mice, which harbor a knock-in of the cDNA encoding the tamoxifen (TAM) inducible CreERT2 recombinase in the Rosa26 gene (Badea et al, J. Neurosci 23:2314-22, 2003). 6-8 week-old mice were injected daily with TAM for 3d (50mg/kg). Mice were sacrificed 10d after the first injection, and splenic B1 and B2 B cell populations sorted by flow cytometry. Splenic B1 and B2 cells from mice with induced deletion of Ikaros
Project description:Humoral immunity in mammals relies on the function of two developmentally and functionally distinct B cell subsets - B1 and B2 cells. While B2 cells are responsible for the adaptive response to environmental antigens, B1 cells regulate the production of polyreactive and low affinity antibodies for innate humoral immunity. The molecular mechanism of B cell specification into different subsets is understudied. We identified lysine methyltransferase NSD2 (MMSET/WHSC1) as a critical regulator of B1 cell development. In contrast to its minor impact on B2 cells, deletion of the catalytic domain of NSD2 in primary B cells impairs the generation of B1 lineage. Thus, NSD2, a histone H3 K36 dimethylase, is the first-in-class epigenetic regulator of a B cell lineage in mice.
Project description:We have comprehensively interrogated wild type B1 and B2 B lineage cells and their progenitors. In mice bearing a conditional deletion of Dnmt3a in the B lineage, we integrated a variety of whole-genome profiling approaches including WGBS, TAB-Seq, RNA-seq, ATAC-Seq and CUT&RUN. The results reveal a stable “foundational methylome” in all B cells that establishes lymphocyte lineage identity. Superimposed on this foundational methylome is a “dynamic methylome” which is differentially modulated in B1 and B2 B cells by the coincident activity/recruitment of DNMT3A and TET enzymes.
Project description:We have comprehensively interrogated wild type B1 and B2 B lineage cells and their progenitors. In mice bearing a conditional deletion of Dnmt3a in the B lineage, we integrated a variety of whole-genome profiling approaches including WGBS, TAB-Seq, RNA-seq, ATAC-Seq and CUT&RUN. The results reveal a stable “foundational methylome” in all B cells that establishes lymphocyte lineage identity. Superimposed on this foundational methylome is a “dynamic methylome” which is differentially modulated in B1 and B2 B cells by the coincident activity/recruitment of DNMT3A and TET enzymes.
Project description:We have comprehensively interrogated wild type B1 and B2 B lineage cells and their progenitors. In mice bearing a conditional deletion of Dnmt3a in the B lineage, we integrated a variety of whole-genome profiling approaches including WGBS, TAB-Seq, RNA-seq, ATAC-Seq and CUT&RUN. The results reveal a stable “foundational methylome” in all B cells that establishes lymphocyte lineage identity. Superimposed on this foundational methylome is a “dynamic methylome” which is differentially modulated in B1 and B2 B cells by the coincident activity/recruitment of DNMT3A and TET enzymes.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.