Littérature scientifique sur le sujet « C16orf35 »

ABSTRACT RNA polymerases can be shared by a particular group of genes in a transcription “factory” in nuclei, where transcription may be coordinated in concert with the distribution of coexpressed genes in higher-eukaryote genomes. Moreover, gene expression can be modulated by regulatory elements working over a long distance. Here, we compared the conformation of a 130-kb chromatin region containing the mouse α-globin cluster and their flanking housekeeping genes in 14.5-day-postcoitum fetal liver and brain cells. The analysis of chromatin conformation showed that the active α1 and α2 globin genes and upstream regulatory elements are in close spatial proximity, indicating that looping may function in the transcriptional regulation of the mouse α-globin cluster. In fetal liver cells, the active α1 and α2 genes, but not the inactive ζ gene, colocalize with neighboring housekeeping genes C16orf33, C16orf8, MPG, and C16orf35. This is in sharp contrast with the mouse α-globin genes in nonexpressing cells, which are separated from the congregated housekeeping genes. A comparison of RNA polymerase II (Pol II) occupancies showed that active α1 and α2 gene promoters have a much higher RNA Pol II enrichment in liver than in brain. The RNA Pol II occupancy at the ζ gene promoter, which is specifically repressed during development, is much lower than that at the α1 and α2 promoters. Thus, the mouse α-globin gene cluster may be regulated through moving in or out active globin gene promoters and regulatory elements of a preexisting transcription factory in the nucleus, which is maintained by the flanking clustered housekeeping genes, to activate or inactivate α-globin gene expression.

Abstract Abstract 4060 Poster Board III-995 Expression of many tissue and developmental stage specific genes is controlled by remote regulatory elements. The mammalian a-globin gene cluster includes four previously characterised remote regulatory elements (MCS-R1 to R4) upstream of the a-globin genes. Naturally occurring deletions and experiments in transgenic mice, have shown that one or more of these elements are necessary for fully regulated expression of the a-like globin genes. At present it is unclear exactly how these elements interact with the a-globin genes to enhance their expression, although ultimately we know that they physically interact with the promoters forming a chromatin loop. Of interest, three of the MCS-R sequences are located within introns of a widely expressed gene C16orf35, which lies adjacent to the a-globin locus and we now know that such complex, intermingled arrangements are common in the mammalian genome. We have asked two questions: can the MCS-R elements be transcribed while activating the globin genes, and does transcription of the MCS-R elements play any role in their activation? We have analysed nascent transcription of C16orf35 and a-globin, and shown that both genes are simultaneously transcribed in a high proportion of erythroid cells. Thus it appears that the MCS-R elements can interact with the globin genes while being transcribed. We next asked whether transcription of the C16orf35 gene (through the upstream regulatory elements) is necessary for their activation. The promoter region and a putative erythroid-specific promoter of the C16orf35 gene were deleted (singly and in combination) by homologous recombination in mice. Provisional analysis has shown no evidence of a-thalassaemia in these mice, suggesting that activation of the MCS-R elements occurs independently of their transcription. In addition to their importance in globin gene regulation, these findings have general implications for the relationship between structure and function in the mammalian genome and the mechanisms by which long-range elements interact with their cognate promoters. Disclosures: No relevant conflicts of interest to declare.

Chromosome 16 open reading frame 54 (C16orf54) is a protein coding gene, showing a biased expression in the bone marrow, lymph node, and 11 other tissues. Reports on the function of C16orf54 in the onset and development of tumours remain scarce. Clinical information and tumour expression profile data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) were utilized to determine the relationship between C16orf54 expression and prognosis, diagnosis, immune microenvironment, heterogeneity, and stemness across pan-cancer. The findings ascertained that C16orf54 was expressed at a low level in most cancers. Furthermore, C16orf54 could distinguish between cancer and normal tissues with high accuracy in most cancers, and the prognostic significance of low C16orf54 mRNA levels differs across cancers. C16orf54 expression was positively linked to the stromal, immune, and ESTIMATE scores. On the other hand, C16orf54 was reported to be negatively correlated with tumour purity in most cancers. Further, C16orf54 expression was positively correlated with immune cell infiltration and the expression of immune regulatory genes, including chemokines, receptors, major histocompatibility complexes, immune inhibitory, and immune stimulatory genes, in most cancers. Additionally, C16orf54 expression was significantly associated with tumour heterogeneity indicators, such as tumour mutation burden (TMB) and microsatellite instability (MSI), and was significantly correlated with DNAss and RNAss tumour stemness indicators. Moreover, Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis, as well as Gene Set Enrichment analysis (GSEA), revealed that C16orf54 expression was closely linked to the signalling pathways of immune cells and factors. The integrated analysis of C16orf54 indicates it as a potential prognostic, diagnostic, and immune marker, which could be adopted as a novel target for adjuvant immunotherapy across pan-cancer.

Aim: Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated. Materials & methods: In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip. Results: Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins. Conclusion: The hypermethylation of cg07326074, located in the tumor-promoting gene C16orf59, was associated with alcohol consumption.

2006/2007
I tumori sono tra le maggiori cause di morte nelle popolazioni occidentali. D'altra parte anomalie congenite nello sviluppo nonostante non siano ugualmente frequenti richiedono uno sforzo notevole in termini di assistenza e cure da parte delle istituzioni e delle famiglie coinvolte. La comprensione dei processi molecolari alla base di queste patologie è quindi di fondamentale importanza per la medicina. Diverse evidenze sperimentali dimostrano come geni coinvolti nello sviluppo embrionale e nel differenziamento sono spesso coinvolto nella genesi dei tumori. In particolare membri della famiglia di p53 rivestono un ruolo fondamentale nell'omeostasi della cellula e le loro funzioni risultano spesso alterate nei tumori ed in alcune malattie genetiche. a livello molecolare l'attività di queste proteine è finemente regolata tramite una serie di modificazioni post-trascrizionali ed interazioni proteiche. Ogni singolo interattore risulta quindi un possibile bersaglio per nuove strategie farmacologiche. In questo lavoro presentiamo la caratterizzazione del prodotto del gene umano c16orf35, un nuovo interattore di p63e p73 isolato da uno screening volto a cercare nuovi interattori di p53 di Drosophila melanogaster. C16orf35 è una proteina nucleare evolutivamente molto conservata ed espressa ubiquitariamente. è in grado di associare con compartimenti cellulari specifici definiti "stress granules" e "p-bodies" in cui gli RNA subiscono diversi tipi di modificazioni strutturali. L'aumento forzato dei livelli cellulari di c16orf35 induce la formazione degli stress granules ed inibisce la proliferazione di cellule tumorali in coltura. Ciò suggerisce un possibile ruolo di questa proteina nelle vie che regolano la crescita cellulare.
1979

The 16p11.2 copy-number variant (CNV) represents a well-characterized, high-risk factor for autism spectrum disorder that additionally predisposes deletion carriers (16pdel) to increased head circumference, known as macrocephaly. The 16p11.2 CNV consists of 29 known genes, many of which are associated with neurobiological processes relevant for macrocephaly such as cell proliferation and apoptosis, differentiation and cell growth. Our lab’s previous work has demonstrated that induced pluripotent stem cell (iPSC)-derived neurons from 16pdel carriers show altered cellular morphology related to growth, which include increased soma size, total dendritic length and dendritic complexity. However, specific CNV genes responsible for these phenotypes have not been established. Here, we investigate the relationship between three 16p11.2 genes and the observed cellular phenotypes. We differentiated neurons from control iPSC-derived neural progenitor cells (NPCs) and used short hairpin RNA (shRNA) to reduce the expression of these CNV genes: KCTD13, MAPK3 and C16ORF53. We then assessed neuronal morphology by evaluating soma size, total dendritic length and dendritic complexity. We demonstrate that knocking down KCTD13 and C16ORF53 increases soma size and total dendrite length, respectively, similar to that observed in 16pdel iPSC-derived neurons. For this reason, we speculate that these genes may have a role in cell growth and might underlie macrocephaly. Thus, our study investigates genes in the 16p11.2 CNV that contribute to neuronal morphology, which may have a role in influencing brain size.

Le matériel génétique (l’ADN) d’un organisme contient l’information nécessaire à sa survie, sa croissance et sa reproduction. La perte de cette information affecte grandement la santé de l’organisme et cette altération est l’un des facteurs les plus courants dans le vieillissement ou le cancer. Quasiment toutes les cellules d’un organisme contiennent une copie de ce matériel génétique, communément appelé le génome, et font usage de plusieurs mécanismes pour en réparer les sections endommagées ainsi que pour le copier avec précision lors de la division cellulaire. Nous avons cherché à étudier les processus cellulaires qui maintiennent la stabilité génomique en inactivant systématiquement chacun des gènes avec la technique de criblage par CRISPR afin d’en étudier les rôles. Nous avons effectué ces criblages à l’échelle du génome dans des lignées cellulaires humaines en combinaison avec des perturbations chimiques dans le but d’identifier l’effet du traitement chimique ou le rôle de gènes qui exacerbent ou atténuent la perturbation. Nous nous sommes d’abord concentrés sur le resvératrol, une molécule initialement extraite de plantes qui a démontré des propriétés antivieillissement dans certains organismes modèles ainsi que la capacité d’inhiber la prolifération cellulaire. Notre criblage génétique a révélé que le resvératrol inhibait la réplication de l’ADN. En comparant les effets cellulaires du resvératrol à l’hydroxyurée, un agent connu pour causer du stress réplicatif, nous avons montré que ces deux traitements menaient à une diminution similaire de la progression de la fourche de réplication ainsi qu’à une activation de la signalisation en réponse au stress réplicatif. Nous avons également démontré que l’inhibition de la réplication de l’ADN dans les cellules humaines par le resvératrol est l’un des effets principaux de la molécule sur la prolifération cellulaire et ne requiert pas la présence de la déacétylase d’histone Sirtuin-1, protéine qui a été suggérée comme étant la cible principale du resvératrol pour son effet antivieillissement. Nous avons également étudié la perturbation d’un second processus cellulaire, soit le maintien des télomères. Ces séquences spéciales aux extrémités des chromosomes sont indispensables à la protection du génome et leur érosion graduelle est contrebalancée par l’activité enzymatique de la télomérase. Nous avons effectué un crible génétique par CRISPR à l’échelle du génome dans une lignée cellulaire dont nous avons inhibé la télomérase en utilisant BIBR1532, un inhibiteur spécifique de la télomérase. Nous avons découvert une forte interaction génétique entre la télomérase et C16orf72, un gène non-annoté que nous avons nommé TAPR1. Nous avons montré que les cellules déficientes en TAPR1 possèdent des niveaux élevés de la protéine p53, un facteur de transcription central à la réponse cellulaire aux dommages télomériques et aux dommages à l’ADN. Nous suggérons que TAPR1 agit comme un inhibiteur de la stabilité protéique de p53. En somme, ces travaux mettent en évidence la capacité des cribles génétiques CRISPR à approfondir nos connaissances sur le fonctionnement des processus de maintien de la stabilité génomique chez l’humain.
The genetic material (DNA) of an organism contains the necessary information for survival, growth and reproduction. Loss of this information strongly impacts the health of the organism and is the leading factor in aging and cancer. Almost all cells in an organism contain a copy of said genetic material (genome) and employ several mechanisms to repair any damaged section of the genome and to accurately copy it during cell division. We sought to understand the cellular processes by which cells maintain genome stability by systematically inactivating individual genes to uncover their role using pooled CRISPR-Cas9 screening. We employed genome-wide CRISPR screening in human cell lines in combination with specific chemical perturbations to identify gene deletions that enhance or suppress the phenotype of the chemical treatment, thereby shedding light on the effect of the treatment or the role of said enhancer/suppressor genes. We first focused on resveratrol; a small molecule first discovered in plants that has been suggested to extend lifespan in model organisms while also inhibiting cell proliferation ex vivo. Chemical-genetic screening pinpointed a role of resveratrol in inhibition of DNA replication. When we compared the cellular effects of resveratrol to hydroxyurea, a known inducer of replicative stress, we found that both treatments led to slower replication fork progression and activation of signaling in response to replicative stress. Importantly, we showed that the inhibition of DNA replication by resveratrol in human cells is a primary effect on cell proliferation and independent of the histone deacetylase Sirtuin-1, which has been implicated as the primary target in lifespan extension by resveratrol. We then studied the perturbation of a second cellular process, namely telomere maintenance. These specialized sequences at the termini of chromosomes are critical for the protection of chromosome ends and their erosion is counteracted by the enzymatic activity of telomerase. We performed a genome-wide CRISPR screen in cells that were concomitantly treated with a specific telomerase inhibitor, BIBR1532. We uncovered a strong genetic interaction between telomerase and a previously unannotated gene, C16orf72, which we named TAPR1. We found that TAPR1-depleted cells led to elevated p53 levels, a transcription factor central for the cellular response to telomeric and global DNA damage. We propose that TAPR1 is a negative regulator of p53 protein levels by promoting its turnover. Altogether, these studies highlight the power of CRISPR-Cas9 in genetic screening to uncover novel insight into the human genome stability maintenance network.