Table 2.

Epigenetic targets in Huntington’s Disease.

Process		Epigenetic targets
DNA methylation	Upregulate	DNA methylation, especially in low CpG content regions [50] Transcriptional regulator SOX2 in low CpG content regions [50] 5-hydroxymethylcytosine levels in the ADORA2A adenosine A2A receptor gene 5′UTR region [51]
	Downregulate	Transcriptional regulator FRA-2 in low CpG content regions [50] Transcriptional regulator JUND in low CpG content regions [50] Transcriptional regulator AP-1 in low CpG content regions [50] 5-methylcytosine levels in the ADORA2A adenosine A2A receptor gene 5′UTR region [51] Alpha thalassemia/mental retardation X linked (ATRX) [52] Cdx-2 (especially activation, or its occupancy at the ATRX promoter) [52]
Histone modification	Upregulate	Chromatin unpacking into a de-repressed unpacked configuration [53] Ubiquitylation of mono-ubiquitylated histone H2A [54] Mono-ubiquitylation of histone H2B [54] Acetylation of histone H2A [55] Acetylation of histone H2B [55] Histone H3 [56] Acetylation of histone H3, especially at lysine 9 [55,57–62] Acetylation of histone H3, especially at lysine 14 [57–62] Acetylation of histone H4 [55,57–62] Acetylation of alpha-tubulin [63] Nuclear histone acetyltransferase (HAT or KAT) [53] CREB-binding protein CBP (KAT3A) [57,58,64] Phosphorylation of CBP [57,58] CREB-regulated transcription coactivator 1 TORC1 [65] p300/CBP-associated factor (P/CAF, or KAT2B) [57,64] Phosphorylation of histone H3 [56,66] Mitogen- and stress-activated kinase-1 MSK1 [66,67] Phosphorylation of MSK1 [56,66] Peroxisome proliferator activator receptor gamma (PPARgamma) [68] PPARgamma coactivator-1alpha (PGC1alpha) [69–71] Phosphorylation of PGC1alpha promoter [67] AMP-activated protein kinase AMPK [72] TAF4 [72] TAF4/CREB complex [72] SIRT1 [65,73,74] SIRT3 [75] Transcription factor p53 [58] in nucleus (not cytoplasm)
	Downregulate	Mono-ubiquitylation of histone H2A [54] Histone methyltransferases Methylation of histone H3, especially at lysine 4 (K4) [54,76] Methylation of histone H3 lysine 9 (K9), especially trimethylation at lysine 9 [54,76–78] ERG-associated protein with SET domain (ESET/SETDB1, also known as KMT1E) [77] DNA binding of specificity proteins Sp1 and Sp3 [77] Huntingtin-interacting protein SETD2/HYPB, responsible for H3K36 trimethylation [79] Histone deacetylases (HDAC) [57,59,76] HDAC1 [80] HDAC2 [81,82] HDAC3 [83] HDAC4 [56,81,82] HDAC5 [55,84] HDAC6 [63] HDAC11 [81,82] SIRT2 [85] Transglutaminase2 [86] Transcription repressor element-1 (RE1) silencing transcription factor (REST, also known as neuron-restrictive silencing factor (NRSF)) [87]
Posttranscriptional RNA editing	Upregulate	Posttranscriptional RNA editing of glutamate receptor GluR-2 [88,89] Posttranscriptional RNA editing of glutamate receptor GluR-6 [88,89]
MicroRNA	Upregulate in presymptomatic and early HD	miR-135b [90] and miR-212 [90,91]
	Downregulate in presymptomatic and early HD	miR-29a [90–92], miR-34b [93], miR-200a [94], and miR-200c [94]
	Upregulate	miR-9 [90,91,95], miR-9* (miR-9A) [90,91,95], miR-22 [96,97], miR-29b [90], miR-29c [96], miR-100 [95], miR-124 [98], miR-124a [90], miR-125b [95,99], miR-128 [96], miR-132 [96,100], miR-135a [95], miR-135b [95], miR-137 [101], miR-138 [95,96], miR-139 [90,91], miR-146a [95,99], miR-150 [95,99], miR-181c [95], miR-190 [95], miR-196a [102], miR-218 [91,95,96], miR-221 [95], miR-222 [95,96], miR-330 [91], miR-338-3p [95], miR-344 [96], miR-485 [103], miR-674 [96], ban [104], let-7a [91], let-7c [91], let-7d [91], and let-7e [91]
	Downregulate	miR-30a [91], miR30b [91], miR-30c [91], miR-30e [91], miR-34b [93], miR-127-3p [95], late HD cortical miR-132 [90,91], miR-145 [95], miR-148a [95], miR-199-3p [95], miR-199-5p [95], miR-200a [95], miR-205 [95], miR-214 [95], and miR-335-5p [95]

Epigenetic targets based on data obtained in Huntington’s disease models, including some targets awaiting replication and establishment. Some of the targets may represent epiphenomena unrelated to HD pathogenesis.