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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

ABSTRACT: Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

SUBMITTER: Dumanski JP

PROVIDER: S-EPMC8106578 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

Dumanski Jan P JP Halvardson Jonatan J Davies Hanna H Rychlicka-Buniowska Edyta E Mattisson Jonas J Moghadam Behrooz Torabi BT Nagy Noemi N Węglarczyk Kazimierz K Bukowska-Strakova Karolina K Danielsson Marcus M Olszewski Paweł P Piotrowski Arkadiusz A Oerton Erin E Ambicka Aleksandra A Przewoźnik Marcin M Bełch Łukasz Ł Grodzicki Tomasz T Chłosta Piotr L PL Imreh Stefan S Giedraitis Vilmantas V Kilander Lena L Nordlund Jessica J Ameur Adam A Gyllensten Ulf U Johansson Åsa Å Józkowicz Alicja A Siedlar Maciej M Klich-Rączka Alicja A Jaszczyński Janusz J Enroth Stefan S Baran Jarosław J Ingelsson Martin M Perry John R B JRB Ryś Janusz J Forsberg Lars A LA

Cellular and molecular life sciences : CMLS 20210410 8

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with ...[more]

PMID: 33837451

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Project description:BackgroundGene promoters have guided evolution processes for millions of years. It seems that they were the main engine responsible for the integration of different mutations favorable for the environmental conditions. In cooperation with different transcription factors and other biochemical components, these regulatory regions dictate the synthesis frequency of RNA molecules. Predominantly in the last decade, it has become clear that nuclear organization impacts upon gene regulation. To fully understand the connections between Homo sapiens chromosomes and their gene promoters, we analyzed 1200 promoter sequences using our Kappa Index of Coincidence method.ResultsIn order to measure the structural similarity of gene promoters, we used two-dimensional image-based patterns obtained through Kappa Index of Coincidence (Kappa IC) and (C+G)% values. The center of weight of each promoter pattern indicated a structure similarity between promoters of each chromosome. Furthermore, the proximity of chromosomes seems to be in accordance to the structural similarity of their gene promoters. The arrangement of chromosomes according to Kappa IC values of promoters, shows a striking symmetry between the chromosome length and the structure of promoters located on them. High Kappa IC and (C+G)% values of gene promoters were also directly associated with the most frequent genetic diseases. Taking into consideration these observations, a general hypothesis for the evolutionary dynamics of the genome has been proposed. In this hypothesis, heterochromatin and euchromatin domains exchange DNA sequences according to a difference in the rate of Slipped Strand Mispairing and point mutations.ConclusionsIn this paper we showed that gene promoters appear to be specific to each chromosome. Furthermore, the proximity between chromosomes seems to be in accordance to the structural similarity of their gene promoters. Our findings are based on comprehensive data from Transcriptional Regulatory Element Database and a new computer model whose core is using Kappa index of coincidence.

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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

Publications

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

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