Year: 2013
Type: article
Abstract: Functional genomics approaches have revolutionized our understanding of biology in the past 20 years or so since microarrays were first pioneered. More recently, next generation sequencing and advanced proteomics methods have provided new insights into many biological questions on a genome-wide scale. In mammalian systems, functional genomics methods tend to be pioneered in ES cells and cells from haematopoiesis and immunity, as these are relatively easily accessible and central to mammalian biology and human health. T cells, B cells as well as other cell types of the adaptive and innate immune systems have been interrogated and characterized by transcriptomics and proteomics methods, both in their steady state and in dynamic processes of development, differentiation or immune response scenarios. Cells of the immune system have also been studied in detail using global methods to unravel their transcriptional regulatory networks and understand their epigenomes. It is probably no exaggeration to say that functional genomics methods are now central to discovery and characterization of the immune system. Functional genomics approaches have been particularly powerful in elucidating transcriptional regulatory networks and the interplay with chromatin in cells of the immune system. For instance, a tour de force of ChIP-sequencing of many histone modifications in T-helper cells provided important insights into the combinatorial action of histone modifications [1], and into their correlation with gene expression levels [2]. The same group pioneered ChIP-sequencing of activating and repressing histone modifications in subsets of T-helper cells [3] and of the transcription factor GATA3 to investigate its binding pattern across different cell types [4]. Moving to the protein level, proteomics by affinity purification coupled with mass spectrometry has provided insights into transcription factor action via binding partners, such as the rich variety of protein complexes involving Foxp3 in regulatory T cells [5]. Proteomics has played an important role through straightforward protein identification. An example is the work on identifying subset-specific protein repertoires in dendritic cell types by mass spectrometry [6]. In this issue of Briefings in Functional Genomics, there are five excellent reviews including one that presents an overview of all the insights afforded by proteomics technologies to T-helper cell differentiation [7]. This includes not only protein abundance and the discrepancies with RNA abundance but also information about post-translational modifications, protein interactions and subcellular localization. Two of the reviews in this issue focus on two sides of the same coin: the (anti)inflammatory response in macrophages [8, 9]. In these responses, signal transduction events trigger large-scale changes in the epigenome, which acts in concert with transcriptional regulatory networks involving conventional sequence-specific DNA-binding transcription factors. While transcription factors generally provide sequence specificity, the importance of the epigenome in the anti-inflammatory response was impressively demonstrated by using a compound to block a reader protein that recognizes acetylated histones [10]. The complex interplay between sequence-specific transcription factors on the one hand and the chromatin level on the other hand is discussed in two further reviews in this issue. Jenner and colleagues describe overarching principles of transcriptional regulation using the model of transcriptional regulatory networks T-helper cells. The concepts put forward in this review are of pioneer factors, synergy versus competition/antagonism between transcription factors, and how these relate to differentiation and plasticity of T-helper cells. Ellen Rothenberg eloquently discusses the earlier upstream development of T cells, and shows how transcription factors and the chromatin status interlink to control this key stage in haematopoiesis. In summary, functional genomics methods continue to be instrumental in advancing our understanding of the development, differentiation, plasticity and communication between cells of the immune system. The cutting-edge next generation sequencing and proteomics methods presented in the reviews here are complementary to two other types of modern biological approaches to immunology: synthetic biology, alluded to above, as well single cell methods, which were reviewed in a recent issue of Briefing in Functional Genomics. Combining single cell resolution with functional genomics methods will be a new frontier for immunology and promises exciting new insights in the years ahead.
Source: Briefings in Functional Genomics
DOI: 10.1093/bfgp/elt037
Author: S. A. Teichmann
Institutions: European Bioinformatics Institute, Wellcome Sanger Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2075763044