Structural maintenance of hinge domain containing 1 (Smchd1) is a noncanonical SMC protein which plays an important role in X-chromosomal as well as autosomal gene repression. Smchd1 targeting to the Xi is known to be dependent on the Xist-HnrnpK-PRC1 pathway, in which Smchd1 recruitment is placed downstream of H3K119 ubiquitylation with no evidence for direct interaction between Smchd1 and H3K119ub. One study reported indirect interactions between Smchd1 and H3K9me marks. However, the importance of these interactions for Xi genes silencing is still controversial. Therefore, the exact hierarchy of epigenetic regulators involved in the mechanism is still not completely unveiled. Furthermore, it remains unclear whether the recruitment of Smchd1 and its silencing mechanism at autosomal targets follow the same pathways as for the Xi targets. Recent studies reported that ablation of Smchd1, in pre-XCI cells, led to the erosion of H3K27me3 on gene bodies, gain of H3K4me3 on the promoters of Xi target genes and upregulation of a subset of these genes. There was an emergence of new type of chromatin compartments on Xi which resembled the A/B compartments on Xa. Intriguingly, our preliminary results, from the analysis of publicly available datasets (mouse ESCs differentiated into NPCs), revealed similar changes in gene expression, H3K27me3, and H3K4me3 marks at Hox clusters. These results suggest that, in NPCs, along with Xi genes Smchd1 is also involved in the silencing of Hox genes. However, the mechanism and correct hierarchy of epigenetic regulators still need to be determined. So, we will further perform genome-wide and targeted multi-omics analysis (RNA expression, histone marks, DNA methylation, chromatin conformation) from public and in-house data sets. This approach will help unravel the interplay amongst various different epigenetic factors involved and the role of chromosome conformation in Smchd1 mediated gene silencing.