Expanded encyclopaedias of DNA elements in the human and mouse genomes

Enhancers can reside in a poised state exhibiting both H3K4me1 and H3K27me3 that is associated with Polycomb repressive complexes.

“In addition to the ‘primed’ and active states, enhancers can also reside in a ‘poised’ state exhibiting both H3K4me1 and H3 lysine 27 trimethylation (H3K27me3) that is associated with Polycomb repressive complexes [131, 135, 136, 138].”

Open chromatin regions are not limited to active enhancers, and also harbour active gene promoters, regulatory elements in a poised chromatin configuration, and some structural regions such as tissue-invariant binding sites for CTCF.

“However, open chromatin regions are not limited to active enhancers, and also harbour other regions including active gene promoters, regulatory elements in a ‘poised’ chromatin configuration (discussed below), as well as some structural regions such as tissue-invariant binding sites for the architectural protein CCCTC-binding factor (CTCF) [129–132].”

Enhancers vastly outnumber promoters in human and mouse genomes, and promoters often contact more than one enhancer in the same cell type.

“Enhancers vastly outnumber promoters in human and mouse genomes [131], and consistently promoters often contact more than one enhancer in the same cell type [141, 243, 278, 279].”

rs1057233 and rs78245530 reside in the candidate cis-regulatory element of SPI1.

“we found that rs1057233 and rs78245530 reside in the candidate cis-regulatory element of SPI1 as revealed by the SCREEN database (Fig. 2d) [34]”

Massively Parallel Reporter Assays have been established to directly test and identify active enhancers.

“new experimental approaches, such as Massively Parallel Reporter Assays (MPRAs), have been established to directly test and identify active enhancers14–18.”

H3K4me3 is typically considered a promoter-associated mark and, in regions proximal to a known transcription start site, has been used to distinguish the enhancer from a promoter.

“In contrast, the trimethylation of histone H3 lysine 4 (H3K4me3) is typically considered a promoter-associated mark and, in regions proximal to a known TSS, has been used to distinguish the enhancer from a promoter [131].”

An element might be classified as a promoter in the cell type-agnostic setting, but as a proximal enhancer-like element in a specific cell type.

“The ENCODE project, for instance, found that an element might be classified as a promoter in the cell type-agnostic setting, but as a proximal enhancer-like element in a specific cell type [131].”

The 12K library included 795 shuffled regions as negative control and 360 positive controls that previously showed activity in HepG2 and have mouse orthologous regions accessible in mouse liver.

“Moreover, we included 795 shuffled regions as a negative control, and 360 positive controls that previously showed activity in HepG2, and for which a mouse orthologous region can be found that is also accessible in the mouse liver.”

Each whole-genome alignment algorithm offers a unique approach and has specific strengths and weaknesses in computational efficiency, scalability, and alignment accuracy.

“Each algorithm offers a unique approach to WGA and has its specific strengths and weaknesses in terms of computational efficiency, scalability, and alignment accuracy [11].”

rs6024870 is located 19bp upstream of an ENCODE candidate cis-regulatory element (ID E2123559).

“Additionally, rs6024870 is located 19bp upstream of an ENCODE candidate cis-regulatory element (ID E2123559)49, further supporting its role as a microglia-specific enhancer.”

Bulk epigenomics data from ENCODE was deconvolved into cell-type assignments using scRNA-seq, refining data annotation.

“Recently, part of its bulk epigenomics data was deconvolved into specific cell-type assignments using scRNA-seq149, which further refines the data annotation.”