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Review
. 2023 Nov;44(11):902-916.
doi: 10.1016/j.it.2023.09.005. Epub 2023 Oct 7.

Interplay between epigenetic and genetic alterations in inborn errors of immunity

Javier Rodríguez-Ubreva  1 , Celia L Calvillo  1 , Lisa R Forbes Satter  2 , Esteban Ballestar  3
Affiliations
Review

Interplay between epigenetic and genetic alterations in inborn errors of immunity

Javier Rodríguez-Ubreva et al. Trends Immunol. 2023 Nov.

Abstract

Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs.

Keywords: epigenetics; inborn errors of immunity; primary immunodeficiencies; transcription factors.

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Conflict of interest statement

Declaration of interests None declared by authors.

Figures

Figure 1.
Figure 1.
Schematic molecular structure of human p105/p50, STAT1, STAT3, STAT6 and IKAROS proteins. Structural domains are shown in boxes: Rel homology domain (RHD), ankyrin repeat domain (ANK), transactivation domain (TAD), N-terminal domain (NTD), coiled-coil domain (CCD), DNA binding domain (DBD), linker domain (LD), Src-homology 2 (SH2) domain, zinc finger (ZF) domain. Selected mutations associated with inborn errors of immunity are indicated (in blue those of gain of function and in red those of loss of function).
Figure 2.
Figure 2.
Scheme depicting the canonical NF-kB and JAK/STAT pathways. Some examples of inborn-errors-of-immunity-associated alterations affecting the proper function of those pathways are shown in boxes. This Figure was created using Biorender.com
Figure 3.
Figure 3.
Scheme depicting the crosstalk between the canonical NF-kB pathway, JAK/STAT pathway and IKAROS with the epigenetic machinery in the context of immune response and immune cell differentiation. Both DNA methylation modulators such as DNMTs and TETs, and chromatin modifiers such as histone deacetylases (HDACs), p300 or G9a, among others, are shown. Top boxes include selected examples of extracellular stimuli that can trigger the activation of the pathway. Arrow represents activation, blunt arrows (⫞) represent repression. DNA methylation is indicated with a circle containing the abbreviations ‘Me’. The corresponding histone modification is indicated inside the ovals on schematic nucleosomes. This Figure was created using Biorender.com
See this image and copyright information in PMC

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