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Enhancers May Govern Cell-Type Specific Expression Patterns

NEW YORK (GenomeWeb News) – Enhancers may have a greater influence on cell-type specific differences in gene expression than promoters or insulators, according to a new study appearing online today in Nature.

A team of researchers from across the US used ChIP-chip analyses and other approaches to map promoter, insulator, and transcriptional enhancer sites and modifications in ENCODE regions of the genome in several human cell lines. In contrast to chromatin occupancy at promoters and CTCF protein-binding at insulators, which were surprisingly similar from one cell type to the next, enhancer modifications varied widely between cell types, in a manner that was consistent with gene expression differences.

By looking across the entire genome of two of the cell lines, the team found more than 55,000 enhancers in the human genome. Overall, they say, their results suggest enhancers may have a greater influence on cell-type specific expression patterns than previously appreciated.

"[W]e found that enhancers are marked with highly cell-type specific modification patterns," senior author Bing Ren, a cellular and molecular medicine researcher at the University of California at San Diego and head of the Ludwig Institute for Cancer Research's Laboratory of Gene Regulation, said in a statement. "These patterns suggested that enhancers are of primary importance in the differentiation of specific cell types."

The LICR's San Diego Epigenome Center at UCSD, which Ren heads, is one of four Reference Epigenome Mapping Centers in the country. Together, the REMCs are involved in a five-year, $190 million, National Institutes of Health-funded program aimed at understanding the epigenome.

Scientists have long puzzled over how cells with the same genome can develop into such a wide range of cell types with different functions. Previous research suggests such cell-type differences are due, in large part, to variable gene expression from one cell type to the next.

At the transcription level, this gene expression is highly regulated, with promoters, enhancers, insulators, and other regulators influencing which parts of the genome get transcribed. But the contribution that each plays to specifying cell type is still poorly understood.

To find promoters, enhancers, and insulators and start teasing apart their effects on gene expression, Ren and his team did a variety of ChIP-chip and other experiments on five different human cell lines using both commercially available and custom antibodies along with NimbleGen tiling and custom-made condensed enhancer microarrays.

First, the researchers assessed chromatin signatures at promoters as well as binding patterns for an insulator-binding protein called CTCF in ENCODE regions of the genomes for all five cell types. Unexpectedly, they found that both histone modifications at promoters and CTCF binding patterns were similar in all cell types tested.

In contrast, when the team looked at transcriptional enhancers in three cell types, using the transcriptional activator protein p300 to identify enhancer sites, they found that histone modifications at enhancers in the ENCODE regions of the genome varied dramatically from one cell type to the next.

Likewise, when assessed additional enhancer sites — identified using chromatin signature predictions, DNase I hypersensitivity, and other enhancer characteristics — the team found that many enhancer sequences were conserved. And again, histone modification patterns at the predicted enhancer sites appeared to be more cell-type specific than either promoter or insulator binding.

"These results indicate that enhancers are the most variable class of transcriptional regulatory element between cell types and are probably of primary importance in driving cell-type specific patterns of gene expression," Ren and his co-authors noted.

In an effort to turn up more previously-unidentified enhancers, the team then applied their ChIP-chip approach to the entire genomes of HeLa cells, a cervical cancer cell line, and K562 cells, a leukemia cell line, mapping enhancers based on known enhancer-related chromatin signatures.

They found more than 55,000 enhancers in the two cell types — 36,589 predicted enhancers in HeLa cells and 24,566 potential enhancers in K562 cells. Consistent with results from ENCODE regions the researchers reported that chromatin modification patterns at enhancers varied by cell type. In addition, these cell-type specific enhancer modifications seemed to correlate with the location of genes that are preferentially expressed in each cell type.

"Our studies show that enhancers play [a] much more prominent role than previously appreciated in cell-type-specific gene expression, helping to explain what causes cells to differentiate into liver or brain or skin cells, or why these cells might become cancerous," Ren said.

And, the team noted, since they found so many enhancers by looking at only two cell types, there are probably many more enhancers sitting undiscovered in the human genome.

"Because enhancers are mostly cell-type-specific, our data indicate the existence of a vast number of enhancers in the human genome ... that are used to drive specific gene expression programs in the 200 cell types in the human body," the authors concluded. "Future experiments with diverse cell types and experimental conditions will be necessary to comprehensively identify these regulatory elements and understand their roles in the specific gene expression program of each cell type."

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