Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration

In the paper

“we identified a significant elevation in cohesin complex expression along with a coordinated increase in DNA damage response in excitatory neurons from subjects with high AD pathology in the large-scale snRNA-seq across 427 AD and control individuals”

In the paper

“Across all genes, both higher transcription levels and increased gene length were significantly associated with increased gene fusions”

In the paper

“genes linked to AD by genome-wide association studies (GWAS) were significantly longer than expected (Figure S3F) and were significantly enriched within fusion genes”

In the paper

“in this study we report an increased burden of mosaic gene fusions in excitatory neurons in individuals with AD pathology by calling fusion events in single-cell RNA-seq in human post-mortem samples in each cell independently”

In the paper

“neurons with acute DSBs had similar levels of structural variations compared to DMSO-treated baseline neurons, whereas neurons with persistent DSBs had a markedly higher frequency of structural variation (201% increase) similar to that of the increase observed in Step 2 neurons”

In the paper

“Step 2 neurons were significantly enriched for gene fusion calls (p-value=5.8e−16) whereas Step 1 neurons showed a modest increase in gene fusions (p-value > 0.05)”

In the paper

“we observed enrichment of DSBs at the gene fusion junctions with the highest enrichment in Control cells, indicating gene-fusion junctions are frequent DSB locations”

In the paper

“gene fusion frequency increased as a function of pseudo time, along with genes associated with senescence, similar to the Step 2 signature”

In the paper

“Step 2 neurons had a much higher frequency of structural variation events (241% increase), whereas the structural variation frequency of Step 1 neurons was similar to that of Control neurons”

In the paper

“snRNA-seq revealed increased gene expression of another nuclear architectural protein Lamin B1 (Lmnb1) in Step 1 neurons and a subsequent decrease in expression from Step 1 to Step 2”

In the paper

“Overall, more loops showed a reduction than a gain in intensity, and loop loss was much more pronounced in Step 2 than in Step 1 neurons”

In the paper

“Thereafter, Lamin B1 intensity decreased after 6 weeks of induction, consistent with the snRNA-seq”

In the paper

“This analysis revealed an overall significant decrease in the TAD definitions in Step 1 that was exacerbated in Step 2”

In the paper

“Reduction in loop intensity was strongly associated with higher percentages of down-regulated genes in both Step 1 and Step 2 neurons and with lower percentages of up-regulated genes”

In the paper

“The enrichment of DSBs at loop boundaries was lowest in Step 1, followed by Step 2”

In the paper

“Hi-C in P301S neurons showed a decreased number of chromatin loops and a significant decrease in TAD integrity as measured by inclusion ratio”

In the paper

“Overall, there was a net decrease in the intensity of long-range interactions above 1 Mb, in Step 1 neurons. This was even more pronounced in Step 2 neurons with the intensity of long-range interactions decreasing from 0.5 Mb”

In the paper

“Immunohistochemistry of Lamin B1 in CK-p25 mice induced for 2 weeks revealed increased Lamin B1 and abnormalities in the structure of Lamin B1 in neurons bearing DSBs.”

In the paper

“approximately 8.5% of the genome shifted compartments and these changes were generally progressive from Step 1 to Step 2”

In the paper

“Another upregulated histone gene, H2AFV, codes for H2A.Z, whose increase is associated with persistent DNA damage, brain aging, and is negatively associated with memory formation”

In the paper

“we found that several histones were upregulated in human AD in excitatory neurons along with the upregulation of the cohesin complex genes”

In the paper

“The 2 hours of treatment with Etoposide was sufficient to induce DSBs, as measured by yH2AX staining (Figure S2G), but not sufficient to accumulate structural variation”

In the paper

“We observed a general loss of TAD definition and loop intensities especially in Step 2 senescence-like neurons along with differential regulation of several genes associated with neuronal identity.”

In the paper

“Changes in the 3D genome aligned with transcriptional changes overall, with reduced loop intensities having a striking correlation with the down-regulation of genes.”

In the paper

“Overall, our work demonstrates that DNA double-strand breaks lead to mosaic genome structural variations and the disruption of 3D genome organization in neurons.”

In the paper

“These results suggest that the persistent DSBs and delayed repair in Step 1 neurons may increase the chance of repair errors and cause them to transition into Step 2 neurons with increased genome structural variations.”

In the paper

“loops with increased intensity did not have a consistent relationship with differential gene expression, suggesting that the association between loop gain and gene expression is context-dependent”

In the paper

“Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.”

• Also stated in: § Introduction · boosted

  “Our results demonstrate the disruption of genome stability and the 3D genome organization mediated by DSBs as pathological steps in the progression of neurodegenerative diseases.”

In the paper

“We show increased gene fusions, genome structural variations, and changes in 3D genome organization in neurons harboring DSBs.”

In the paper

“NEHJ is error-prone and can cause genome structural variations, potentially leading to gene fusions with pathological gain or loss of function”

What the sources say

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In the paper

“structural variations have the potential to rewire genes with ectopic regulatory elements”

What the sources say

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In the paper

“Chromatin accessibility has also been shown to be disrupted in the AD brain”

What the sources say

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In the paper

“There is now emerging evidence that the 3D genome is actively regulated during learning and memory formation”

What the sources say

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In the paper

“The cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair”

What the sources say

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In the paper

“cohesin has been shown to protect against genome structural variations”

What the sources say

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In the paper

“disease-associated SNPs in non-coding areas of the genome influence genes associated with diseases including Alzheimer’s Disease (AD)”

What the sources say

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In the paper

“the disruption of 3D genome organization has been demonstrated in neurodevelopmental and neurological neurodegenerative disorders such as Huntington’s disease, Fragile X syndrome, Down syndrome, etc.”

What the sources say

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In the paper

“the accompanying manuscript by Xiong et al. describes widespread changes in cell-type specific chromatin accessibility within excitatory neurons in human AD samples which they term “epigenome erosion””

What the sources say

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In the paper

“Chromatin loops enable interactions between enhancers and promoters enabling fine control of gene expression, in addition to the regulation mediated by transcription factors and other epigenetic modifications”

What the sources say

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In the paper

“Lamin B1 has been shown to control the release of DSB repair protein 53BP1 and overexpression of LaminB1 impeded DSB repair leading to persistent DSBs”

What the sources say

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In the paper

“loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting Topologically Associating Domains (TADs)”

What the sources say

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In the paper

“loop boundaries are hotspots for TOP2 B-mediated DNA breaks in T-cells and B-cells”

What the sources say

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In the paper

“Lamin B1 plays a crucial role in the 3D genome organization by tethering heterochromatin to the nuclear periphery”

What the sources say

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In the paper

“While the A compartment is largely localized to the nuclear interior, the B compartment is tethered to the nuclear periphery by Lamin B1”

What the sources say

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In the paper

“We propose that the increased stochastic DSB burden strains the DNA repair resources, leading to defective DNA repair and genome structural variations that disproportionately affect hotspots of DNA breaks such as highly expressed genes, long genes, and loop anchors.”

In the paper

“For instance, a neo-TAD caused by structural variation was associated with higher expression of the oncogene MYC in neuroblastomas23.”

What the sources say

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In the paper

“Indeed, genomic mosaicism by retro transposition of LINE-1 elements has been associated with the neuronal genome and the derepression of LINE-1 elements has been associated with senescence129–131.”

What the sources say

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In the paper

“genome structural variations can lead to gene fusions and are often drivers of cancer”

What the sources say

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In the paper

“Interestingly, erosion of epigenetic information, TAD insulation, and cell identity was recently reported in a mouse model with inducible DNA damage (ICE mouse model) accompanied by brain aging and cognitive decline132.”

What the sources say

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In the paper

“Surprisingly, X-ray radiation-induced DSBs increased the segregation of TAD fibroblasts54.”

What the sources say

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In the paper

“Surprisingly, Step 1 showed lower DSB enrichments for highly transcribed and long genes, and DSBs were supported by fewer UMIs, suggesting that Step 1 DSBs are largely stochastic.”

In the paper

“These observations combined with our results suggest that genomic mosaicism is an important driver of senescence in neurons and could contribute to the pathogenesis of neurodegenerative disease.”

In the paper

“Recently, a study identified an increase in mosaicism due to recombination between Alu and L1 elements in Parkinson’s and Alzheimer’s disease120.”

What the sources say

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In the paper

“Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions in neurodegeneration)124–128.”

What the sources say

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In the paper

“Interestingly, genome structural variations have been shown to cause pathological TAD fusions and create neo-TADs in several cancers.”

What the sources say

• Not checked yetcites [23] Dixon JR, Xu J, Dileep V, Zhan Y, Song F, Le VT, Yardımcı GG, Chakraborty A, Bann DV, Wang Y, (2018). Integrative detection and analysis of structural variation in cancer genomes. Nat. Genet. 10.1038/s41588-018-0195-8. PMC6301019 30202056 source

In the paper

“A recent study proposed that DSBs can act as roadblocks to loop extrusion32.”

What the sources say

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In the paper

“accumulation of DNA damage can lead to a senescence-like state in neurons and has been implicated in the progression of AD”

What the sources say

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In the paper

“DSBs are repaired via the classical non-homologous end joining (NHEJ) pathway in post-mitotic cells and can lead to genome structural variations”

What the sources say

• Not checked yetcites [18] Richardson C, and Jasin M (2000). Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697– 700. 10.1038/35015097. 10864328 source
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In the paper

“In the current study, we are unable to resolve the precise role of each of these components.”

In the paper

“Bio-replicate 1 of Step 2 neurons was excluded from the analysis of differential A/B compartment statistical significance owing to its lower read depth.”

In the paper

“The disruption in the 3D genome organization could be caused both directly by unresolved DSBs and by genome structural variations.”

In the paper

“Additionally, studies have shown senescence-associated 3D genome reorganization in dividing cell types42,140–143.”

What the sources say

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In the paper

“We quantified the enrichment of putative fusion events at the cell level across conditions using a negative binomial generalized linear model where we model the number of fusions in each cell with an offset term for the number of reads captured for that cell (log(n_counts)).”

In the paper

“Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation100–102,136–139.”

What the sources say

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• Not checked yetcites [136] Isermann A, Mann C, and Rübe CE (2020). Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence. Int. J. Mol. Sci. 21, 1– 20. 10.3390/IJMS21239130. PMC7729917 33266246 source
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• Not checked yetcites [139] Funk OH, Qalieh Y, Doyle DZ, Lam MM, and Kwan KY (2022). Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity. Proc. Natl. Acad. Sci. U. S. A. 119. 10.1073/pnas.2116956119. PMC9371731 35930666 source

In the paper

“Three replicates were performed, where each replicate was a pool of 3 CK-p25 mice forebrains (Table S1, page 16).”

In the paper

“All the experiments were approved by the Committee for Animal Care of the Division of Comparative Medicine at the Massachusetts Institute of Technology (MIT) and carried out at MIT.”

In the paper

“At least two coronal slices were used for each mouse for image quantification.”

In the paper

“While relatively uncommon, chimeric molecules arising through PCR artifacts and random ligations during library preparation are difficult to distinguish from chimeric molecules arising from true mosaic gene fusions.”

In the paper

“We removed the ‘SM_171013Tsa’ batch from the original dataset due to markedly lower quality, number of reads, and number of genes detected per cell.”

In the paper

“We fitted a linear mixed-effects model with the percentage of high RAD21 neurons or mean intensity of RAD21 as the response variable, group (Control or AD) as the fixed effect, and individual (ID) as the random effect.”

In the paper

“Single-cell RNA seq provides a sparse readout of gene expression and is likely to generally underestimate the number of gene fusions in each cell.”

In the paper

“For single-nucleus Smart-seq2, we selected a subset of 47 individuals comprised of 24 and 23 age and sex-matched cases with AD pathology (NIA-Reagan 1–2) and no pathologic AD (NIA-Reagan 3–4).”

In the paper

“Informed consent was obtained from each subject, and the Religious Orders Study and Rush Memory and Aging Project were each approved by an Institutional Review Board (IRB) of Rush University Medical Center.”