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Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.
Introduction: One third of Chronic Lymphocytic Leukemia (CLL) patients harbor stereotyped B-Cell receptor (BCR). This is in contrast with the 1012 potential different BCRs that can be produced by the immune system. Some stereotyped BCR are also highly associated with prognosis. For example, the stereotyped subset #2 identifies aggressive CLLs with frequent SF3B1 and ATM alterations. This underlies an important role of BCR selection for emergence of CLL clones. Aim and methods: We raised the question of the existence and quantification of B-cells with stereotyped BCR of the CLL-type in a series of 69 healthy subjects (HS) from 18 to 78 years old, without any past of hematological history nor any detectable monotypic B-cells by flow cytometry. HS were divided in age three groups, adults (18 - 55 years, n= 31), senior-1 (55 - 65 years, n = 14) and senior-2 (> 65 years, n = 24). The variable region of the immunoglobulin heavy chain gene (IGHV) was amplified from genomic DNA of purified B-cells sequenced on an Illumina MiSeq and annotated with the online IMGT HighV-Quest tool. Clonotypes were defined as IGHV genes with the same rearranged V and J segment and with the same CDR3 amino acid sequence with one mismatch tolerance, and if a minimal threshold read number was reached (ranging 5 to 15 according to the DNA input and sequencing depth).Public clonotypes were those shared in between at least 4 (5%) HS. Detection of the 19 major stereotyped CLL's BCRs was performed with an in house R script. And was confirmed with the ARResT/AssignSubsets online tool (V Bistry et al, Bioinformatics, 2015). Exploration of the IGHV repertoire of the different B-cell subpopulations was done from public data (Mitsunaga, Mol Cell Proteomics, 2020). Results: To be independent of the number of reads and to compare HS to each other, clonotypic frequencies were ranked in 150 increasing intervals. In each case, the mean rank of clonotypic frequency ranged 3 to 7 with an SD in between 2 and 6 and was independent of the age category. A Z-score was calculated for each clonotype. Less than 1% of private clonotypes had a Z-score>1.96, while 10% to 30% of public clonotypes had a significant Z-score>1.96 (figure 1). This indicates that public clonotypes are often accumulated when compared to their private counterpart. A stereotyped CLL's BCR was found in 90% HS all stereotypes together. Subsets #2 and #5 were found in more than 50% of cases (figure 2). Frequencies of subsets #3, #59, #7C, #202, #14, #64B, decreased from 23% to 6% cases. Subsets #1, #4, #6, #8, #12, #16, #99 and #201 were never found. Frequencies of stereotyped BCRs ranged 5.2x10 -5 to 1.2x10 -4, being similar in the different HS age categories. Ranks of stereotyped BCR frequencies were almost always below the mean rank of private clonotypes, that indicates a very low abundance (figure 3). Junction analyses suggest that B-cells with stereotyped BCRs were polyclonal since they were very likely to derive from different B-cell precursors. Exploring the longitudinal repertoires of Mitsunaga and Snyder(Mol Cell Proteomics 2020), showed that stereotyped BCRs were almost restricted to immature and naïve B-cells and were fugace while public clonotypes were recurrently and frequently found in memory B-cells and could be stable over time for many of them. Conclusion: B-cells with stereotyped CLL BCRs were easily detected in healthy people whatever their age category. Remarkably, subsets #2 and #5 that are associated with aggressive CLL were found in more than 50% healthy donors at any age. Comparison with private and public clonotypic repertoire reveals that abundance of stereotyped BCR was almost always very low and was restricted to immature and naïve B-cells. Therefore, B-cells with stereotyped BCRs are produced throughout life in almost everybody. But these B-cells do not accumulate and do not seem to undergo to B-cell maturation. This suggests that stereotyped BCRs are not intrinsically prone to transformation and that clonal selection of CLL cells would involve additional events such as antigenic encounter or oncogenic alterations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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