The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients.
Sarah C PyfromBam Dev PaneruJames J KnoxMichael P CancroSylvia E PossoJane H BucknerMontserrat C AngueraPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.
Keyphrases
- systemic lupus erythematosus
- gene expression
- single cell
- dna methylation
- disease activity
- genome wide
- endothelial cells
- rna seq
- induced pluripotent stem cells
- end stage renal disease
- rheumatoid arthritis
- ejection fraction
- newly diagnosed
- chronic kidney disease
- copy number
- high throughput
- peripheral blood
- machine learning
- type diabetes
- big data
- prognostic factors
- young adults
- metabolic syndrome
- induced apoptosis
- peritoneal dialysis
- transcription factor
- adipose tissue
- poor prognosis
- genome wide identification
- quantum dots
- cell death
- heat shock
- oxidative stress
- skeletal muscle
- bioinformatics analysis
- cell therapy
- long non coding rna
- cell proliferation
- heat shock protein
- patient reported outcomes
- energy transfer
- cell cycle arrest