Loss of ASXL1 expression is associated with lymph node metastasis in colorectal cancer.

CONTEXT: The function of ASXL1 in colorectal cancer (CRC) has not been investigated yet. AIMS: The purpose of this study was to investigate the clinicopathological and prognostic impact of ASXL1 expression on CRC. SETTINGS AND DESIGN: The intensity of expression was scored as 0-3, and the extent of staining was scored as 0-4, based on the percentage of positive cells. The immunoreactivity score (IRS) was calculated by multiplying the two scores. MATERIALS AND METHODS: We performed immunohistochemical staining of ASXL1 using tissue microarrays of 408 CRCs, 46 normal colonic mucosae, 48 adenomas, and 92 metastatic lymph nodes. STATISTICAL ANALYSIS USED: Clinicopathological variables were compared using Fisher's exact test, χ2-test, or unpaired Student's t-test, depending on the nature of the data. RESULTS: A negative expression of ASXL1 was observed in 10.9% of normal mucosae, 27.1% of adenomas, 55.6% of adenocarcinomas, and 71.7% of metastatic lymph nodes (P < 0.001). With respect to the IRS cut-off score, lymph node metastasis and lymphatic invasion were more frequent in the IRS 0-6 group than in the IRS 8-12 group (56.3% vs. 33.3%, P = 0.034; 56.0% vs. 33.3%, P = 0.035). The 5-year disease-free survival rate was significantly lower in patients with IRS 0-6 group than those with IRS 8-12 group (78.7 ± 2.5 vs. 100%, P = 0.034). CONCLUSION: ASXL1 might act as a tumor suppressor in CRC. The loss of ASXL1 expression might be associated with lymph node metastasis and lymphatic invasion in CRC.

NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance to irreversible human alopecia, which also displays reduced NFIs. Through single-cell transcriptomics, ATAC-Seq and ChIP-Seq profiling, we expose a key role for NFIB and NFIX in governing super-enhancer maintenance of the key hair follicle SC-specific TF genes. When NFIB and NFIX are genetically removed, the stemness epigenetic landscape is lost. Super-enhancers driving SC identity are decommissioned, while unwanted lineages are de-repressed ectopically. Together, our findings expose NFIB and NFIX as crucial rheostats of tissue homeostasis, functioning to safeguard the SC epigenome from a breach in lineage confinement that otherwise triggers irreversible tissue degeneration.