Defining Patient-Level Molecular Heterogeneity in Psoriasis Vulgaris Based on Single-Cell Transcriptomics.

Identifying genetic variation underlying human diseases establishes targets for therapeutic development and helps tailor treatments to individual patients. Large-scale transcriptomic profiling has extended the study of such molecular heterogeneity between patients to somatic tissues. However, the lower resolution of bulk RNA profiling, especially in a complex, composite tissue such as the skin, has limited its success. Here we demonstrate approaches to interrogate patient-level molecular variance in a chronic skin inflammatory disease, psoriasis vulgaris, leveraging single-cell RNA-sequencing of CD45+ cells isolated from active lesions. Highly psoriasis-specific transcriptional abnormalities display greater than average inter-individual variance, nominating them as potential sources of clinical heterogeneity. We find that one of these chemokines, CXCL13, demonstrates significant correlation with severity of lesions within our patient series. Our analyses also establish that genes elevated in psoriatic skin-resident memory T cells are enriched for programs orchestrating chromatin and CDC42-dependent cytoskeleton remodeling, specific components of which are distinctly correlated with and against Th17 identity on a single-cell level. Collectively, these analyses describe systematic means to dissect cell type- and patient-level differences in cutaneous psoriasis using high-resolution transcriptional profiles of human inflammatory disease.

SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1.

The SAM-pointed domain-containing ETS transcription factor (SPDEF) is an epithelial-specific transcription factor of the E26 transformation-specific (ETS) family, which binds the target gene through the high-affinity sequence of GGAT. It is suggested that SPDEF targets the promoter activity of Forkhead Box M1 (FoxM1), which has been proven to be highly expressed in gastric cancer. We found that SPDEF was overexpressed both at the messenger RNA (mRNA) and at the protein level in human gastric cancer species. The gastric cancer cells transfected with the SPDEF expression plasmid or SPDEF small interfering RNA (siRNA) led to observations on the clone genetics assay that indicated the promotion or the inhibition of gastric cancer cell proliferation, respectively. Both mRNA and protein levels of FoxM1 were regulated by SPDEF in gastric cancer cells and FoxM1 was also overexpressed in the corresponding human gastric cancer species. The overexpression and inhibition of FoxM1 could upregulate and downregulate the mRNA and protein levels of SPDEF expression, respectively. The recovery experiments verified that the overexpression of FoxM1 could at least partially revert both the expression of SPDEF and the proliferation of the cell lines even with the siRNA inhibition of SPDEF. The result of the dual luciferase activity assay showed that SPDEF bound to the promoter of FoxM1 and activated it. FoxM1 might also bind to the promoter of SPDEF to affect its expression. The results were checked in vivo. In conclusion, SPDEF is overexpressed in gastric cancer, which can form a positive regulation loop with FoxM1 to promote gastric carcinogenesis.