Background: Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer’s disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD. Methods: To investigate histone H3 modifications in AD, we compared the genome-wide distributions of H3K4me3 and H3K27me3 in entorhinal cortices from severe sporadic AD patients and from age-matched healthy individuals of both sexes. Results: AD samples were characterized by typical average levels and distributions of the H3K4me3 and H3K27me3 signals. However, AD patients showed a lower H3K4me3 and higher H3K27me3 signal, particularly in males. Interestingly, the genomic sites found differentially trimethylated at the H3K4 between healthy and AD samples involve promoter regions of genes belonging to AD-related pathways such as glutamate receptor signaling. Conclusions: The signatures of H3K4me3 and H3K27me3 identified in AD patients validate the role of epigenetic chromatin remodeling in neurodegenerative disease and shed light on the genomic adaptive mechanisms involved in AD.

Members of the tripartite motif family of E3 ubiquitin ligases are characterized by the presence of a conserved N-terminal module composed of a RING domain followed by one or two B-box domains, a coiled-coil and a variable C-terminal region. The RING and B-box are both Zn-binding domains but, while the RING is found in a large number of proteins, the B-box is exclusive to the tripartite motif (TRIM) family members in metazoans. Whereas the RING has been extensively characterized and shown to possess intrinsic E3 ligase catalytic activity, much less is known about the role of the B-box domains. In this study, we adopted an in vitro approach using recombinant point- and deletion-mutants to characterize the contribution of the TRIM32 Zn-binding domains to the activity of this E3 ligase that is altered in a genetic form of muscular dystrophy. We found that the RING domain is crucial for E3 ligase activity and E2 specificity, whereas a complete B-box domain is involved in chain assembly rate modulation. Further, in vitro, the RING domain is necessary to modulate TRIM32 oligomerization, whereas, in cells, both the RING and B-box cooperate to specify TRIM32 subcellular localization, which if altered may impact the pathogenesis of diseases.

Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis through a tightly regulated balance of self-renewal, proliferation and differentiation, particularly under stress conditions.Here, we identify PRDM15, a transcription factor with well described roles in early embryonic development, as a crucial regulator of hematopoiesis during stress responses. While PRDM15 deletion is tolerated at steady state in adult hematopoiesis, its absence severely impairs bone marrow reconstitution following transplantation, causing sustained reduction in bone marrow cellularity and differentiation blocks. Notably, PRDM15-deleted bone marrow exhibited an accumulation of stem and progenitor cells, indicating a block in lineage differentiation. Furthermore, in competitive transplantation assays, PRDM15-deficient cells were unable to compete with wild-type counterparts, demonstrating a profound loss of fitness.Transcriptomic and epigenomic analyses reveal PRDM15 as a critical regulator of differentiation and proliferation of HSCs. Mechanistically, PRDM15 directly regulates the expression of several key genes involved in proliferation and differentiation pathways, including the transcription factor Cux1 . Cux1 overexpression partially rescues colony-forming ability of PRDM15-deficient HSCs.These findings establish PRDM15 as a pivotal stress-responsive regulator of HSC differentiation and survival, with implications for therapeutic modulation of hematopoiesis.