Aging chromosome

E2F1, HDAC1 go down with age, associated with Steiner S3. But their interchromosome connections are non-obvious
Chromosome changes are fastest in the very old
CEBPB and REEPB5 were marked as significant…

resulting intermingling difference map among all loci is shown in Figure 3c. Interestingly, almost all intrachromosomal LAS submatrices were shared among young and old fibroblasts (Figure 3d(i), overlap of 99.995%), while 15.5% of the interchromosomal intermingling regions were specific to either the old cell state or the young cell state (Figure 3d(ii)). The rearrangements between the young and old states at the chromosome level are shown in Figure S14D and examples of difference maps are provided for chromosome 17 in cis (Figure S11A) and for the chromosome pair 17-19 in trans (Figure 3e and Figure S11B). In the latter, one LAS submatrix was present only in the young condition (colored in blue) and one submatrix only in the old condition (colored in magenta). These results suggest that the intrachromosomal chromatin organization is rather stable during aging, and the chromatin reorganization is mostly happening via changes in interchromosomal contacts. Although interchromosomal interactions have been less studied in the past compared to intrachromosomal chromatin interactions, there has been increasing evidence supporting their role in cell type-/state-specific gene regulation (Maass et al., 2019).

Next, we visualized the changes in the network of Hi-C contacts between a TF and its target genes for the significant bridge TFs with the highest percentage of age-associated changes in the intermingling of their target genes (CEBPB in the Steiner network S1 and RBBP5 in the Steiner network S3). This metric, along with the target enrichment p-value corresponding to each TF, are reported in the z-scored heatmap for all bridge TFs in S1 (Figure 5c(i)) and S3 (Figure 5c(ii)); for additional features for each TF such as the number of target genes or the number of protein–protein interactions (PPIs) in the Steiner networks see Figure S19. The selected TFs are interesting because they are key to bridging the DE genes between the young and old conditions and their gene targets undergo 3D organizational changes during aging. The corresponding networks are shown in Figure 5d and Figures S20 and S21. The subnetwork associated with CEBPB consists of 66 nodes and 214 intermingling interactions (edges), out of which 8.4% are young-specific and 12.1% are old-specific. Interestingly, CEBPB has two intermingling interactions with its target genes that were only found in young or old cells (young-specific = blue edges, old-specific = magenta edges in Figure 5d(i)). CEBPB has been described in a previous study as a key regulator of energy metabolism and longevity (Xia et al., 2021). In the subnetwork associated with RBBP5, 14.2% of the 1084 edges between the 62 nodes are young-specific and 1.5% are old-specific, with RBBP5 having three young-specific intermingling interactions with its target genes (Figure 5d(ii)). This high amount of young-specific intermingling between the downregulated targets of RBBP5, which has been associated to the age-driven loss of H3K4 methylation (Yuan et al., 2015), supports the hypothesis that these genes might be co-activated in the young state and are less expressed in the old state, potentially due to the loss of spatial clustering between them.

RBBP5 goes up with age but not hugely

one should expect increase in association of bivalent promoters (which often gain methylation with age…) These are especially associated with maximum lifespan in animals…

RBBP5 has so many young interacting targets


some time ago i saw a poster on super-enhancers. have to revisit that and see if superenhancers are associated with this paper

this paper is SO unlike any other i’ve seen ebfore so I feel it’s important. But its also very very unintuitive (i mean the data is v. messy and it’s just skin)…

WikiCrow | Future House to summarize function of some of these TFs, but still doesn’t hit on which TFs interact w/each other (which is important for function)

Bivalent promoters are characterized by the simultaneous presence of both activating (H3K4me3) and repressive (H3K27me3) histone modifications

hypermethylation of bivalent promoters and agnig…

H3K4me3 at bivalent promoters—a product of the underlying DNA sequence—persists in nearly all cell types irrespective of gene expression and confers protection from de novo DNA methylation. Bivalent genes in ESCs that are frequent targets of aberrant hypermethylation in cancer are particularly strongly associated with loss of H3K4me3

histone (hyper)methylation is NOT the same as epigenetic (hypermethylation), the histone methylation is supposed to prevent the corresponding epigenetic sites from being hypermethylated?

Genome-wide studies in differentiating ESCs reveal that activation of bivalent genes is no more rapid than that of other transcriptionally silent genes, challenging the premise that H3K4me3 is instructive for transcription. H3K4me3 at bivalent promoters—a product of the underlying DNA sequence—persists in nearly all cell types irrespective of gene expression and confers protection from de novo DNA methylation

Hi Alex,
Speaking of aging chromosomes, are you familiar with LOY? (Loss of chromosome Y)

It has over the last decade accumulated a strong case to be the causative reason why the average lifespan of men is significantly lower than that of women.

I took the liberty to use SciSpace to compile some of the research on the subject:
LOY loss of Y and aging - SciSpace Literature Review (