Trends in Immunology
Feature ReviewExploiting genomics and natural genetic variation to decode macrophage enhancers
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Exploiting macrophages to understand enhancer biology and enhancer biology to understand macrophages
Macrophages (see Glossary) are phagocytic cells of the innate immune system that reside in all tissues of the body and play key roles in responding to infection and injury through signaling downstream of pattern recognition receptors 1, 2, 3. In addition to these general roles that operate throughout the body, each tissue-resident population of macrophages performs specific effector functions that contribute to the homeostasis of that tissue 2, 4. Some of the diverse roles that macrophages have
The million enhancer question
All cells in the body contain essentially the same genome. The mechanisms that govern how different cell types uniquely interpret the same set of instructions, and thereby achieve specialized functional roles, are incompletely understood. In recent years, it has become clear that on the genome scale, DNA sequences called enhancers, more so than promoters, orchestrate the majority of cell-type-specific patterns of gene expression 25, 26, 27, 28, 29. Although the distinction between enhancers and
General features of enhancers
Enhancers are discrete regions of the genome that function to increase transcription from nearby promoters [31] (reviewed in 32, 33). In the pre-genomics era, enhancers were first identified as stretches of DNA that, when inserted up- or downstream of transgenes, were able to augment gene expression irrespective of orientation [31].
In eukaryotes, DNA is wrapped around nucleosomes into chromatin, which serves as a regulatory barrier to transcription factors. Enhancer elements are bound by
Enhancer selection by LDTFs
Enhancer selection is defined here as the process by which an enhancer element in the genome is converted from an inactive to a primed, poised, or active state. Important classes of transcription factors, called pioneer transcription factors or LDTFs, are able to initiate enhancer selection by competing with nucleosomes to bind their DNA recognition motifs and establish a nucleosome-free region. This process is accompanied by concurrent or subsequent recruitment of chromatin-modifying enzymes
Chromatin dynamics
Chromatin dynamics in hematopoietic development has proven to be a powerful system to study enhancer state transitions during lineage specification 21, 61, 75. Hematopoiesis initiates with the self-renewing multipotent hematopoietic stem cell (HSC) that differentiates into either the common lymphoid progenitor (CLP) or common myeloid progenitor (CMP) [76]. CMPs further differentiate into lineage-committed progenitors called megakaryocyte–erythroid progenitors (MEPs) or granulocyte–macrophage
LDTFs direct signal responsiveness
Enhancer selection by LDTFs results in primed enhancers, but may not result in active enhancers (as measured by acetylation on histone H3 tails at lysine 27, or H3K27ac [45] and enhancer transcription 46, 47).
The transition to an active enhancer state can either be initiated from a primed state, whereby lineage factors have already established a nucleosome-free region, or from an inactive or closed state 32, 61, 86 (Figure 3). Both mechanisms of enhancer activation involve collaborative
Testing enhancer selection models using natural genetic variation
A collaborative and hierarchical model for selection and activation of cell-specific enhancers provides a framework for understanding how genetic variation perturbs enhancer function and target gene expression with cell specificity. The concept that enhancers are major determinants of cell-specific gene expression is central to the interpretation of certain types of noncoding variants associated with disease risk. Conversely, natural genetic variation can be used as a genome-wide ‘mutagenesis
Using natural genetic variation to discover regulatory networks
Macrophages are important effector cells that reside in every tissue of the body [4]. Their diverse functions in different tissue environments as well as their essential roles in health and disease make them an important experimental system to study chromatin priming, signal integration, and cooperative interactions at enhancers. To this end, transcriptomes and primed and active enhancers were compared between macrophages resident in diverse tissues in mice 19, 20, 21. Different macrophage
Implications for human disease
Recent advances in the field of gene regulation on the genome-wide scale, such as emergent properties of enhancer selection and activation by different classes of transcription factors, have valuable applications in the field of human genetics. The observation that the majority (∼88%) of risk loci for common diseases in genome-wide association studies (GWASs) are outside of the protein-coding genome [110] certainly necessitates insightful strategies for elucidating the functional sequence
Concluding remarks
Rapid progress is being made with respect to how enhancers function; nonetheless, many challenges remain (Box 2). For example, the ability to predict transcription factor binding and enhancer selection based on DNA sequence and knowledge of expressed transcription factors is a distant goal. Predicting the consequences of transcription factor binding is also problematic. One challenging observation, for instance, is that the binding of NF-κB to an enhancer can result in an increase, decrease, or
Glossary
- C/EBP
- a family of basic-leucine zipper (bZIP) transcription factors that bind DNA and form homo-and heterodimer interactions. C/EBPα and C/EBPβ are LDTFs in macrophages.
- ChIP-Seq
- chromatin immunoprecipitation followed by high-throughput sequencing. This assay identifies the genomic location and frequency with which a particular protein or histone modification associates with DNA.
- Chromatin
- DNA that is wrapped around nucleosomes. Chromatin compaction is dynamic with spatiotemporal patterns dependent
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