Table 2.

Epigenetic landscape modifications and functional impact on chromatin of ALS TDP-43 mutations.

TDP-43 Mutation		Epigenomic Alterations	Cellular Context	Refs.
G294V	DNA damage/DSB TC-DSB	Mislocalization;	SH-S5Y5	[97]
		R-loop accumulation; R-loop-dependent increased DSBs
		Accumulation of FANCD2 repair foci (replication blockage).
G298S	DNA methylation	Hyper- and hypo-methylated regions related to controls with common and specific DMRs related to other ALS hIPSCs-derived MNs (C9orf72-, TARDBP-, SOD1-, and FUS-mutation carriers).	hIPSCs-derived MNs from G298S carrier	[74]
A315T	Chromatin remodeling	Diminution of nBAF chromatin-remodeling complex components (Brg1, BAF53b, and CREST).	Cultured mouse MNs	[57]
	DNA methylation	Altered 5mC and 5hmC underlying their increased vulnerability to degeneration.	TDP-43A315T mouse CSMNs	[171]
	DNA damage/DSB	Enhanced vulnerability to DNA damages.	MN-like NSC-34 cells	[95]
M323K	Autoregulation	Increased RNA, but not significant for protein.	Mouse TDP-43M323K knock-in	[167]
Q331K	Autoregulation	Increase in RNA and nuclear protein in frontal cortex and spinal cords of mutant mice, but not in motor neuron.	Mouse TDP-43Q331K knock-in but not transgene	[168,169]
	DNA damage/DSB	Increased cytosolic sequestration of the poly-ubiquitinated and aggregated form, nuclear loss of function DNA damage induction, and DSB repair defects (preventing the nuclear translocation of XRCC4); Contribution to oxidative genome damage accumulation via increased reactive oxygen species (ROS).	Spinal cord of ALS Q331K carriers, SH-S5Y5	[93]
		Enhanced vulnerability to DNA damages (increase yH2Ax post damaging agent exposure).	MN-like NSC-34 cells	[95]
M337V	DNA methylation	No global alteration in 5mC	SH-S5Y5	[58]
	Histone PTMs	Significant decrease in global H3S10Ph-K14Ac; No significant increase in H3K9me3.
	DNA damage/DSB	Impairment in the NHEJ DSB repair factors recruitment.	Fibroblasts of human M337V carrier	[95]
G348C	Autoregulation	Upstream intron1 promoter region of TARDBP binding but less efficient than WT for its repression; No significant activation of the intron 1 promoter.	HEK293T	[170]
A382T	DNA Methylation	No global alteration in 5mC.	SH-S5Y5	[58]
	Histone PTMs	No significant decrease in global H3S10Ph-K14Ac; No significant increase in H3K9me3.
	DNA damage/DSB TC-DSB	Increased yH2Ax; R-loop accumulation; R-loop-dependent increased DSBs accumulation of FANCD2 repair foci (replication blockage).	SH-S5Y5 LCL from A382T carriers	[97]
	Isoforms/fragments	Increased TDP-35 form at chromatin at R-loop.	LCL from A382T carriers	[97]
	Autoregulation	Upstream intron1 promoter region of TARDBP binding but less efficient than WT for its repression; Able to induce a significant activation of the intron 1 promoter.	HEK293T	[170]
N390D	DNA methylation	Hyper- and hypo-methylated regions related to controls with common and specific DMRs related to other ALS hIPSCs-derived MNs (C9orf72-, TARDBP-, SOD1-, and FUS-mutation carriers).	hIPSCs-derived MNs from N390D carrier	[74]
G418C	Chromatin remodeling	Diminution in nBAF chromatin-remodeling complex components (Brg1, BAF53b and CREST).	Cultured mouse MNs	[57]
C9orf72 with loss of nuclear TDP-43	DNA methylation	Altered DNA 5mC and 5hmC in the CSMN without nuclear TDP-43 compared to residual C9orf72 CMSN without TDP-43 nuclear loss.	Residual lower MNs from post-mortem CSMN tissues of C9orf72 carriers	[73]

MNs: motor neurons; CSMNs: corticospinal MNs; LCL: lymphoblastoid cell line.