An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome

Abstract

ICF syndrome has been described as the association of variable immunodeficiency, facial anomalies and centromeric heterochromatin instability. Since the chromosome rearrangements seen in cells of ICF patients are reminiscent of the chromosomal changes induced by the undermethylating agent 5-azacytidine in the late S-phase, we have analyzed the methylation pattern of satellite sequences in four patients. These sequences are almost completely methylated in normal leukocyte DNA. When ICF DNA was tested with methyl-sensitive enzymes, several classical satellite families, but not alphoid sequences, showed a very low level of methylcytosine in leukocyte DNA, with an abnormal pattern compared to the normal germinal and extraembryonic methylation profile. The methylation deficiency affects classical satellite families built from distinct unit sequences but located in the same chromosomal region. This observation may have important implications for the mechanism of chromosomal rearrangements.

DNA hypomethylation is prevalent even in low-grade breast cancers

“…Alternatively, our findings for fibroadenomas vs. normal control tissues might reflect atypical tissue-specific differences. 38 Sat2 hypomethylation at Chr1 and Chr16 is related to rearrangements in cis in the ICF syndrome (immunodeficiency, centromeric region instability, and facial anomalies) 15,16 and significantly associated with Chr1 pericentromeric rearrangements in hepatocellular carcinomas. 20 Moreover, in normal lymphoid cells, the DNA methylation inhibitors 5-azacytidine or 5-azadeoxycytidine specifically induce pericentromeric rearrangements especially in the longest region of Sat2, which is at 1qh.…”

“…14 Interestingly, Sat2, Sat3, and Satα are hypomethylated in sperm DNA, and Sat2 and Sat3 are also invariably hypomethylated in cells from patients with the ICF syndrome (immunodeficiency, centromeric region instability, and facial anomalies; a DNA methyltransferase 3B deficiency disease). 10,11,[15][16][17] Studies of ICF lymphoid cells and normal cells treated with DNA methylation inhibitors suggest that DNA hypomethylation can favor pericentromeric rearrangements, including the formation of unstable multiradial chromosomes that may give rise to stable, unbalanced cancer-like DNA rearrangements. 15,16,18,19 This is consistent with a comparative genomic hybridization study showing a significant association between 1qh gain and Chr1 Sat2 hypomethylation in hepatocellular carcinomas.…”

“…10,11,[15][16][17] Studies of ICF lymphoid cells and normal cells treated with DNA methylation inhibitors suggest that DNA hypomethylation can favor pericentromeric rearrangements, including the formation of unstable multiradial chromosomes that may give rise to stable, unbalanced cancer-like DNA rearrangements. 15,16,18,19 This is consistent with a comparative genomic hybridization study showing a significant association between 1qh gain and Chr1 Sat2 hypomethylation in hepatocellular carcinomas. 20 Because pericentromeric rearrangements of Chr1 and Chr16 are overrepresented in diverse cancers and often lead to 1qh gain and 16qh loss, 21 they could participate in tumorigenesis or tumor progression.…”

DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations

“…6,7 ICF cells are characterized by several molecular defects. Non-coding repetitive sequences (ie, satellites 2 and 3, subtelomeric sequences, and Alu sequences) [8][9][10] and genes located in constitutive and facultative heterochromatin (hereafter named C-heterochromatin and F-heterochromatin, respectively) are hypomethylated. 11,12 This loss of DNA methylation is associated with chromatin decondensation and chromosome instability.…”

Subcellular distribution of HP1 proteins is altered in ICF syndrome

“…In ICF patients, there is therefore constitutive hypomethylation of satellite 2 DNA, mostly located at the juxtacentromeric heterochromatin of chromosomes 1 (1qh) and 16 (16qh), and of satellite 3 DNA which is mostly located at the 9qh heterochromatin. 5,6 The cytogenetic abnormalities detectable in mitogen-stimulated lymphocytes, as well as in lymphoblastoid cell lines, are specifically targeted to these heterochromatic regions and include marked elongation of juxtacentromeric heterochromatin, multibranched chromosome configurations, centromeric breakages, whole arm chromosome deletion or duplication and micronuclei containing acentric fragments. Such observations have led to the suggestion that hypomethylation of satellite DNAs induces alterations in the structure, condensation and stability of the heterochromatin in these regions.…”