EFB Dengue Literature Review

EGR

3 min read

EGR

Overview

The Early Growth Response (EGR) family comprises four zinc-finger transcription factors (EGR1, EGR2, EGR3, EGR4) that are rapidly induced in response to diverse cellular stimuli including BCR stimulation. EGR proteins have been implicated in autoimmunity, plasma cell differentiation, and B cell development. In the epigenetic analysis of SLE B cells by Scharer et al. (2019), EGR factors were identified at the apex of the SLE disease transcriptional network — their target genes were enriched in 19 of 22 (86%) gene sets upregulated in SLE.

Key Points from Literature

  • EGR4 is the highest-scoring TF in the SLE disease network: PageRank analysis of ATAC-seq and RNA-seq data identified 31 transcription factors enriched in ≥3 SLE B cell subsets. EGR4 had the highest PageRank score, indicating its central importance to the SLE transcriptional state (see Scharer2019 - Epigenetic Programming in SLE B Cells, multi-omic PageRank analysis, n=9 SLE + n=12 HC).
  • EGR1 and EGR2 validated by independent cohort qPCR: RT-qPCR of resting naive B cells from an independent cohort showed significant upregulation of EGR1 (P=0.024) and EGR2 (P=0.005) in SLE vs. HC. EGR3 and EGR4 had minimal expression in resting naive cells (P=0.87 and P=0.78 respectively) — consistent with their induction being activation-dependent (see Scharer2019 - Epigenetic Programming in SLE B Cells, n=15 HC, n=8 SLE).
  • EGR motifs enriched in DN2 chromatin: EGR motifs were among the top enriched motifs in accessible chromatin of DN2 cells compared with isotype-switched memory cells. DN2 cells had the highest levels of chromatin accessibility at EGR motifs of any B cell subset, with activated naive cells also showing high accessibility (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • EGR target genes span 86% of SLE-upregulated pathways: Mapping EGR target genes to GSEA gene sets showed enrichment in 19/22 upregulated SLE pathways, including MTORC1, MYC targets, G2/M checkpoint, DNA repair, estrogen response, hypoxia, oxidative phosphorylation, apoptosis, inflammatory response, complement, TNF signalling, UPR, and peroxisome pathways (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • EGR1 and EGR4 networks are remarkably overlapping: Analysis of individual EGR family member networks showed high connectivity and overlap between EGR1 and EGR4, suggesting co-regulation of the same transcriptional targets (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • EGR1 ChIP-seq peaks overlap SLE DARs: ENCODE ChIP-seq data for EGR1 showed significant overlap with SLE-specific differentially accessible chromatin regions (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • EGR factors also regulate other TFs in the network: EGR target genes included other transcription factors in the SLE network, placing EGR at the apex of a hierarchical regulatory cascade (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • Known roles in B cell biology: EGR proteins are induced by BCR stimulation, have been linked to autoimmunity (including SLE susceptibility polymorphisms in EGR2), and regulate plasma cell differentiation (see Scharer2019 - Epigenetic Programming in SLE B Cells, citing Gomez-Martin et al. 2010, Oh et al. 2015, Gururajan et al. 2008, Myouzen et al. 2010).

Contradictions & Debates

None documented in current wiki sources.

ATF3, T-bet, DN2 B Cell, Activated Naive B Cell, Extrafollicular Response

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