Abstract:Gene silencing in cancer frequently involves hypermethylation and dense nucleosome occupancy across promoter regions. How a promoter transitions to this silent state is unclear. Using colorectal adenomas, we investigated nucleosome positioning, DNA methylation, and gene expression in the early stages of gene silencing. Genome-wide gene expression correlated with highly positioned nucleosomes upstream and downstream of a nucleosome-depleted transcription start site (TSS). Hypermethylated promoters displayed inc… Show more
“…S8, Supplementary Material online). For the remaining two promoter categories ( Low and Intermediate ), we find 3- to 200-fold weaker signal powers of Fourier periodicity, in line with their known, less pronounced, nucleosome occupancy and phasing patterns in living cells (Hesson et al 2014). F ig .…”
The first epigenomes from archaic hominins (AH) and ancient anatomically modern humans (AMH) have recently been characterized, based, however, on a limited number of samples. The extent to which ancient genome-wide epigenetic landscapes can be reconstructed thus remains contentious. Here, we present epiPALEOMIX, an open-source and user-friendly pipeline that exploits post-mortem DNA degradation patterns to reconstruct ancient methylomes and nucleosome maps from shotgun and/or capture-enrichment data. Applying epiPALEOMIX to the sequence data underlying 35 ancient genomes including AMH, AH, equids and aurochs, we investigate the temporal, geographical and preservation range of ancient epigenetic signatures. We first assess the quality of inferred ancient epigenetic signatures within well-characterized genomic regions. We find that tissue-specific methylation signatures can be obtained across a wider range of DNA preparation types than previously thought, including when no particular experimental procedures have been used to remove deaminated cytosines prior to sequencing. We identify a large subset of samples for which DNA associated with nucleosomes is protected from post-mortem degradation, and nucleosome positioning patterns can be reconstructed. Finally, we describe parameters and conditions such as DNA damage levels and sequencing depth that limit the preservation of epigenetic signatures in ancient samples. When such conditions are met, we propose that epigenetic profiles of CTCF binding regions can be used to help data authentication. Our work, including epiPALEOMIX, opens for further investigations of ancient epigenomes through time especially aimed at tracking possible epigenetic changes during major evolutionary, environmental, socioeconomic, and cultural shifts.
“…S8, Supplementary Material online). For the remaining two promoter categories ( Low and Intermediate ), we find 3- to 200-fold weaker signal powers of Fourier periodicity, in line with their known, less pronounced, nucleosome occupancy and phasing patterns in living cells (Hesson et al 2014). F ig .…”
The first epigenomes from archaic hominins (AH) and ancient anatomically modern humans (AMH) have recently been characterized, based, however, on a limited number of samples. The extent to which ancient genome-wide epigenetic landscapes can be reconstructed thus remains contentious. Here, we present epiPALEOMIX, an open-source and user-friendly pipeline that exploits post-mortem DNA degradation patterns to reconstruct ancient methylomes and nucleosome maps from shotgun and/or capture-enrichment data. Applying epiPALEOMIX to the sequence data underlying 35 ancient genomes including AMH, AH, equids and aurochs, we investigate the temporal, geographical and preservation range of ancient epigenetic signatures. We first assess the quality of inferred ancient epigenetic signatures within well-characterized genomic regions. We find that tissue-specific methylation signatures can be obtained across a wider range of DNA preparation types than previously thought, including when no particular experimental procedures have been used to remove deaminated cytosines prior to sequencing. We identify a large subset of samples for which DNA associated with nucleosomes is protected from post-mortem degradation, and nucleosome positioning patterns can be reconstructed. Finally, we describe parameters and conditions such as DNA damage levels and sequencing depth that limit the preservation of epigenetic signatures in ancient samples. When such conditions are met, we propose that epigenetic profiles of CTCF binding regions can be used to help data authentication. Our work, including epiPALEOMIX, opens for further investigations of ancient epigenomes through time especially aimed at tracking possible epigenetic changes during major evolutionary, environmental, socioeconomic, and cultural shifts.
“…2). Deletions of chromosome 1p, 5q, 14q, and 18 and duplications of chromosome 7,8,13,19, and 20 represent some of the most common changes seen in colonic and rectal adenocarcinomas ( Fig. 2).…”
Section: Discussionmentioning
confidence: 99%
“…RNA-Seq was performed as described previously (8) using the HOMER package (9) and the trimmed mean of m-value method (10). Significant differential expression between LST and normal tissue was determined using DESeq (ref.…”
Section: Rna-seqmentioning
confidence: 99%
“…However, on average, only 28.5% of these aberrations correlated with loss of gene expression, defined as >2-fold downregulation relative to paired normal mucosa (ref. 8; hereafter referred to as epigenetic inactivation). This corresponded to a median of 225 epigenetically inactivated genes (mean, 225; range, 53-564, Fig.…”
Section: Identification Of Genes Altered In Lsts Relative To Paired Nmentioning
“…Altered promoter nucleosome positioning is an early event in gene silencing [ 83 ]. The term positioning describes the precise location of a given nucleosome, whereas occupancy describes the proportion of molecules bearing a nucleosome at a specifi c location, at any given instant [ 84 ].…”
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