Transcriptional Control of Lineage Differentiation in Immune Cells

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Laboratory Dominic Grün

When a cell differentiates becomes more specialized , it may undertake major changes in its size, shape, metabolic activity, and overall function. Because all cells in the body, beginning with the fertilized egg, contain the same DNA, how do the different cell types come to be so different? The answer is analogous to a movie script. The different actors in a movie all read from the same script, however, they are each only reading their own part of the script. In biology, this is referred to as the unique genetic expression of each cell.

In order for a cell to differentiate into its specialized form and function, it need only manipulate those genes and thus those proteins that will be expressed, and not those that will remain silent. A transcription factor is one of a class of proteins that bind to specific genes on the DNA molecule and either promote or inhibit their transcription Figure 2.

Stem Cell Research Stem cell research aims to find ways to use stem cells to regenerate and repair cellular damage. Over time, most adult cells undergo the wear and tear of aging and lose their ability to divide and repair themselves. Stem cells do not display a particular morphology or function. Adult stem cells, which exist as a small subset of cells in most tissues, keep dividing and can differentiate into a number of specialized cells generally formed by that tissue.

These cells enable the body to renew and repair body tissues. The mechanisms that induce a non-differentiated cell to become a specialized cell are poorly understood. In a laboratory setting, it is possible to induce stem cells to differentiate into specialized cells by changing the physical and chemical conditions of growth. Several sources of stem cells are used experimentally and are classified according to their origin and potential for differentiation.

Human embryonic stem cells hESCs are extracted from embryos and are pluripotent. The adult stem cells that are present in many organs and differentiated tissues, such as bone marrow and skin, are multipotent, being limited in differentiation to the types of cells found in those tissues. The stem cells isolated from umbilical cord blood are also multipotent, as are cells from deciduous teeth baby teeth. Researchers have recently developed induced pluripotent stem cells iPSCs from mouse and human adult stem cells.

These cells are genetically reprogrammed multipotent adult cells that function like embryonic stem cells; they are capable of generating cells characteristic of all three germ layers. Because of their capacity to divide and differentiate into specialized cells, stem cells offer a potential treatment for diseases such as diabetes and heart disease Figure 3. Cell-based therapy refers to treatment in which stem cells induced to differentiate in a growth dish are injected into a patient to repair damaged or destroyed cells or tissues.

Many obstacles must be overcome for the application of cell-based therapy. In this volume, leading experts provide an up-to-date and comprehensive overview of recent advances in the transcriptional control mechanisms and transcription factor networks that regulate these processes in a variety of different immune cell lineages.

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The chapters cover the regulation of T versus B cell lineage choice, discuss early B cell development and pre-B cell leukemia prevention, address transcriptional control mechanisms during the differentiation, in regulatory T cells and iNKT cells, detail genomic switches in helper cell fate choice and plasticity and highlight the role of the BTB-zinc finger family of transcription factors in T cells. Moreover, the chapters discuss transcriptional networks in DCs, NK cells and in innate lymphoid cells.

Together, the reviews illustrate key transcriptional control mechanisms that regulate the development and function of immune cells and demonstrate the impressive advances made over the last decade. Wilfried Ellmeier, PhD. Taniuchi Ichiro, M. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. Epigenetic profiling was performed using the following 16 cell samples isolated from 7 healthy donors: including 7 aTreg, 4 rTreg, 2 Teff, 2 Tmem, and 1 Tn independently isolated cell populations.

See also Figure 1—figure supplement 1A,B. Mice injected with DT underwent punctual Treg cell depletion and consequent transient systemic inflammation, which resulted in activation of rebounding Treg and conventional T cells. D , E Genetic and epigenetic conservation at select loci. Multiple regulatory elements near LRRC32 and YY1 are genetically and epigenetically conserved: YY1 has two epigenetic elements that are not conserved in human; LRRC32 has a regulatory element that is genetically, but not epigenetically conserved.

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D Acetylation at the LRRC32 locus shows multiple conserved genetic elements that illustrate concordant and discordant epigenetic states across species highlighted regions. Orthologous regions with regulatory elements of interest are shown by blue background highlighting and red connecting lines.

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A genetically conserved element near LRRC32 is epigenetically active in mouse, but not in human leftmost highlighted region. E Two regulatory elements near YY1 are epigenetically active in human but are not genetically conserved in mouse leftmost and rightmost highlighted regions. F Genome-wide fractions of genetically conserved acetylated loci. Loci with high read counts are more frequently genetically conserved shown as are regulatory elements more proximal to gene body Figure 1—figure supplement 1H.

G Genome-wide quantification of epigenetic conservation. Axes show H3K27ac quantification reads per million: RPM of murine x-axis and human y-axis acetylated loci. This histone modification serves as a reliable marker for active regulatory elements Creyghton et al. In addition to histone acetylation, we incorporated previously generated DNase-seq hypersensitive site DHS data sets to enable higher resolution positioning of active acetylated regulatory elements Arvey et al. We found that the overall epigenetic features of chromatin in human- and mouse-activated Treg cells were highly conserved based on qualitative and quantitative analyses.

We identified loci that were genetically and epigenetically conserved e. A similar correlation was revealed by analyses of chromatin accessibility at DHSs across organisms Figure 1—figure supplement 1J. We reasoned that the most critical genetic components of the Treg lineage identity would be genetically and epigenetically conserved in mouse and human and additionally be Treg lineage-specific in both species.

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We thus characterized regulatory elements with conserved lineage-specific activity, which we defined as increased or decreased H3K27ac amounts in Treg cells in comparison to non-Treg cells in both mouse and human. This was an extension of the above analyses in which we characterized genetic conservation of regulatory elements and the epigenetic activity of these elements in mouse and human Treg cells.

Previous studies of multiple cell lines and specialized tissues from different organisms have shown that non-coding regulatory elements are more likely to be genetically conserved and active based on their epigenetic features Bernstein et al. However, it remained unclear whether cell lineage-specific regulatory elements, which define identity and function of a given cell type, are conserved at genetic, epigenetic, and lineage-specific functional levels Cheng et al. We identified a handful of regulatory elements with cell lineage-specific acetylation in both human and mouse.

Intriguingly, while the genome-wide epigenetically active landscape was similar in human and mouse, quantification of cell lineage specificity revealed that very few of the elements are Treg cell-specific in both species Figure 2B and Figure 2—figure supplement 1A—C. A The LRRC32 locus contains multiple epigenetically active regulatory elements that are conserved and Treg lineage-specific in mouse and human. B Lineage-specific conservation of epigenetic activity occurs at only a handful of Treg regulatory elements.

C Treg cell lineage-specific gene expression is similarly conserved as lineage-specific chromatin features in mouse and man. Changes in gene expression in aTreg compared to Teff cells are shown for mouse x-axis and human y-axis cells. D Conserved gene expression changes are associated with conserved lineage-specificity of histone acetylation. Expression changes are shown for genes most proximal to regulatory elements that were lineage-specific in both species. See also Figure 2—figure supplement 2.

E Species-specific gene expression changes are associated with species-specific changes in histone acetylation. Acetylated loci were classified as upregulated or downregulated in a cell type-specific manner in mouse, human, or both organisms. These loci were mapped to their most proximal gene expressed in either mouse or human lines and cumulative fraction is shown y-axis.

Genetic and epigenetic variation in the lineage specification of regulatory T cells

The differential expression in aTreg vs Teff cells was plotted for these genes in human left and mouse right. Regulatory elements that are lineage-specific in both species dashed lines have been associated with genes with the most conserved differential expression patterns. Statistical significance was assessed by the Kolmogorov—Smirnov test; all relevant distribution shifts are statistically significant; p-values are shown for relevant comparisons in Figure 2—figure supplement 1F.

Comparison of lineage-specific gene expression revealed similar conservation of gene expression patterns.

We also observed that organism-specific cell lineage-associated variation in H3K27 acetylation correlated with organism-specific gene expression changes Figure 2D,E and Figure 2—figure supplement 1F. The latter result is consistent with organism-specific regulatory elements maintaining functional impact on Treg cell lineage-specific epigenetic activity.

Namely, previous studies have identified broad conservation of the regulatory networks even if the exact regulatory elements and transcription factor-binding sites are not conserved Stergachis et al.

Transcriptional Control of Lineage Differentiation in Immune Cells

This implies that lineage specification of Treg cells is governed by a specific evolutionarily constrained small set of regulatory elements, which is in contrast to the more plastic conservation of global genome-wide regulatory network architectures Stergachis et al.

Given the critical role of Foxp3 in establishment and maintenance of Treg cell identity and function, and Treg-specific chromatin repression Arvey et al. We quantified Foxp3 binding in human and murine Treg cells and found that many Foxp3-bound loci were genetically conserved and bound in both organisms Figure 3A , Figure 3—figure supplement 1A,B ; Supplementary files While there was substantial conservation of Foxp3 binding, there were also many sites that were species specific or had insufficient binding for robust quantification in the weaker Foxp3-bound sites in one of the species Figure 3B.

A The TCF7 locus provides examples of conserved first intron, promoter-proximal , mouse-specific upstream , and human-specific first intron, promoter-distal Foxp3 binding. Plot layout and axes are similar to Figure 2A. Orthologous regulatory elements light blue and their orthological mapping red are shown. B Genome-wide, regulatory elements are bound by Foxp3 in both mouse and human red or in a human-specific green or mouse-specific blue manner.

This locus contains species-specific Foxp3-binding sites that are associated with species-specific decrease in acetylation in Treg cells marked as 1, 3 and conserved Foxp3 binding that is associated with conserved Treg lineage decreases in acetylation 2. The decrease in acetylation at the PDE3B promoter is conserved in both species.

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D Conserved and species-specific Foxp3 binding is associated with decreased histone H3K27 acetylation at regulatory elements. Changes in human or mouse H3K27 acetylation y-axis at genetically conserved regulatory elements are shown to be associated with human- or mouse-specific, or conserved Foxp3 binding x-axis. E Species-specific Foxp3 binding in mouse and human Treg cells is associated with non-conserved forkhead box DNA motif.

Enrichment of the forkhead motif odds ratio, y-axis is shown for those Foxp3-binding sites that are genetically conserved and bound only in human left or mouse center Treg cells or both right. Odds ratio and statistical significance were calculated using Fisher's exact test, where motif counts in Foxp3-binding sites were compared to flanking nt regions to estimate the empirical enrichment over chance.

Recent reports have implicated Foxp3 in repression of chromatin Arvey et al. Importantly, at human- or mouse species-specific Foxp3-bound sites, H3K27ac was decreased exclusively in the corresponding organism Figure 3D , Figure 3—figure supplement 1D. Species-specific Foxp3 occupancy at genetically conserved loci was also associated with presence of forkhead DNA-binding motifs at the corresponding Foxp3-bound sites Figure 3E. These results suggest that preservation of the forkhead motif likely enables Foxp3 protein recruitment, Foxp3-mediated chromatin repression at conserved loci, and that DNA sequence divergence can account for differential Foxp3 occupancy of otherwise genetically conserved orthologous regulatory elements.

Epigenetic Control of Immunity

To determine if non-coding regulatory elements specific to resting or activated Treg cells are subject to genetic variation in human, we explored polymorphisms associated with these elements. This pattern held across regulatory elements regardless of their distance from protein-coding regions or binding of Foxp3 Figure 4—figure supplement 1A—C.

D Quantification of the ENTPD1 genetic association reveals allele-specific histone modification in heterozygous individuals. Genotypes x-axis and their corresponding reads crossing the polymorphism per million reads aligned RPM; y-axis were calculated for each individual with more than 5 reads at rs Values across zygosity and cell type were made comparable by doubling heterozygous RPMs and mean normalizing.

To test if genetic variation in the Treg cell-specific regulatory elements could alter enhancer functionality, we characterized DNA sequence polymorphisms associated with inter-individual quantitative variability in H3K27ac modifications across multiple cell populations in a cohort of unrelated donors Figure 4—figure supplement 1D,E. For example, the Treg cell lineage-specific enhancer containing the single nucleotide polymorphism SNP rs at the ENTPD1 locus demonstrated genetic association with H3K27ac levels across individuals and in an allele-specific manner in a given individual Figure 4C.

We confirmed the genetic association with chromatin state through meta-analysis of lymphoblastoid cell lines, which enabled sufficient statistical power Figure 4D. Our observation that the inter-individual genetic variation present in the Treg cell-specific epigenome can potentially alter Treg cell function raised a question if this variation may contribute to polygenic human disease pathogenesis.

Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells
Transcriptional Control of Lineage Differentiation in Immune Cells Transcriptional Control of Lineage Differentiation in Immune Cells

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