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Upinox Trades Nigeri Group

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1 Novo


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1 Novo


Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1:ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.


Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.


Mechanisms of de novo mutations. De novo mutations can arise because of static properties of the genome, such as the underlying sequence (deamination of methylated CpGs, transitions versus transversions) or due to erroneous pairing of nucleotides during DNA replication. However, de novo mutations can also occur in relation to cell-specific properties such as the chromatin state, transcriptional status, and gene expression levels. Mutational hotspots for genomic rearrangements are largely determined by the underlying genomic architecture. One such example is given for non-allelic homologous recombination (NAHR). Arrows represent the influence of each feature on the de novo mutation rate. Green arrows pointing upwards indicate elevated mutability; red arrows pointing downwards indicate lower mutability. M methyl group modifying cytosine


In this review, we first touch on the biological aspects of de novo mutations in humans, such as their origin, distribution throughout the genome, and factors related to their occurrence and timing. Later, we discuss the increasingly recognized role of de novo mutations in human disease and other translational aspects. Throughout, we will focus mostly on de novo SNVs; readers should refer to Box 2 and previous work from others for more information on the role of de novo CNVs and other structural genomic variation in human disease [36, 37].


The difference between the rate at which pre-mutagenic damage appears in DNA and the rate at which it is repaired defines the rate at which de novo mutations arise. It is often assumed that germline de novo mutations originate from errors in DNA replication during gametogenesis, particularly in sperm cells and their precursors (see section below on parental origin of de novo mutations). However, inefficient repair of spontaneous DNA lesions can also give rise to de novo mutations during spermatogenesis, as continuous proliferation and short periods between cell divisions can translate into there being less time to repair these lesions [44, 45]. Furthermore, in oogenesis, spontaneous DNA mutations coupled to inefficient repair mechanisms might play a more prominent role [44]. Therefore, while the de novo mutation rate is a reflection of the replication error rate and the number of mitoses a cell has undergone, this number is also influenced by the amount of time between mitoses and the efficiency of the DNA repair [44].


Another origin for some of these clusters could be chromosomal rearrangements. It has been shown that the mutation rate for SNVs is elevated and SNVs can cluster in proximity to the breakpoints of de novo CNVs [62, 63]. This is likely the result of the replicative CNV mechanism in which a low-fidelity, error-prone DNA polymerase is used during repair of DNA. Indeed, work performed in yeast supports the observation that double-strand-break-induced replication is a source of mutation clusters [61].


In contrast to the mutation clusters that occur within one individual, mutational hotspots are considered overlapping loci that are found to be mutated more frequently than expected in different individuals. Recent research based on WGS datasets and modeling has identified such hotspots in coding sequences [9]. Furthermore, the existence of these mutational hotspots has been recently confirmed in a larger study that showed specific bins of 1 Mb within the human genome with elevated mutation rates [13]. Interestingly, in this study, two bins including genes CSMD1 and WWOX were shown to have a higher maternal than paternal mutation rate. The mechanism for this is still largely unknown, but the latter is a well-known fragile site within the human genome [64]. Other sites of the human genome that are especially prone to de novo mutations include ribosomal DNA (rDNA) gene clusters [65], segmental duplications [66], and microsatellites [67], with mutation rates three to four orders of magnitude higher than average [68].


Approximately 80% of all de novo germline point mutations arise on the paternal allele, and advanced paternal age at conception has been established as the major factor linked to the increase in the number of de novo mutations in the offspring, both at the population level and within the same family (Fig. 2) [11, 13, 15]. Spermatogonial cells continue to divide throughout life, which is likely to allow the progressive accumulation of mutations due to errors during DNA replication but also as a result of failure to repair non-replicative DNA damage between cell divisions [44]. Furthermore, the efficiency of endogenous defense systems against radical oxygen species and of DNA repair mechanisms might also decline with age [71, 72]. De novo mutations in children of young fathers show a different signature and localize to later-replicating regions of the genome compared with those of children of old fathers, suggesting that additional factors contribute to de novo mutations with age [12, 13]. It has been calculated that one to three de novo mutations are added to the germline mutational load of the offspring for each paternal year at conception, but this effect varies considerably between families [11, 13]. This variability has been suggested to be due to individual differences in the rate of mutagenesis, in the frequency of spermatogonial stem cell division and even to genetic variation in DNA mismatch repair genes [11]. Indeed, one could speculate that deleterious variation in genes involved in replication and repair could predispose to elevated de novo mutation rates not only in somatic cells but also in the germline, as has been observed in mouse models lacking exonuclease activity in DNA polymerase δ [73].


Timing of de novo mutations (DNMs). Sperm cells have undergone approximately 100 to 150 mitoses in a 20-year-old man, whereas oocytes have gone through 22 mitoses in a woman of the same age (left). As a result of errors in both replication of the genome and repair of DNA damage occurring during parental embryogenesis, gametogenesis, or as postzygotic events in the offspring, DNMs arise in each new generation. Advanced parental age is associated with an increase in the number of de novo mutations (right). The male germline adds 23 mitoses per year, entailing that a spermatogonial stem cell in a 40-year-old man has undergone more than 600 cell mitoses. Each additional year in paternal age at conception adds one to three de novo mutations to the genome of the offspring. Oogenesis has a fixed number of mitoses, but mutations accumulate over time possibly owing to failure to repair DNA damage. The increase in number of de novo mutations with maternal age is lower: 0.24 extra de novo mutations for each additional year of maternal age at conception. Cell lineages modified from [238]. Somatic cells are showed in orange, the male germline is shown in blue, and the female germline is shown in purple. Blue stars represent postzygotic mutations present in the germline and in somatic cells; yellow stars represent mutations arising exclusively in the germline; red stars represent somatic mutations arising during embryonic development or post-natal life which are absent from germline cells. Figure footnotes: 1The ratio of paternal to maternal mutations originating from parental gonosomal mosaicism is 1:1; 2the ratio of paternal to maternal germline de novo mutations is 4:1; 3the ratio of paternal to maternal postzygotic de novo mutations is 1:1; 4this range is based on the average number of de novo mutations published elsewhere [9, 10, 12, 13, 15] irrespective of parental age


Following the identification of genomic regions enriched for maternal de novo mutations [13], the possibility of selfish mutations in the maternal germ line has also been put forward [72]. It appears that these genomic regions harbor genes with a role in tumor suppression, and some de novo mutations could, it is speculated, provide mutant oocytes in aging women with a survival advantage over wild-type ones [72]. 59ce067264






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