EFB Dengue Literature Review

ATF3

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ATF3

Overview

ATF3 (Activating Transcription Factor 3) is a member of the ATF/CREB family of transcription factors that is induced in response to BCR stimulation, TLR signalling, and cellular stress. ATF3 functions as a transcriptional repressor when bound as a homodimer but can heterodimerize with Jun family members (JUN, JUNB, JUND) to function as an activator. In the context of B cell biology, ATF3 was identified as a key SLE-specific regulator of the DN2 B cell transcriptional network by Scharer et al. (2019).

Key Points from Literature

  • Maximally expressed in SLE DN2 B cells: ATF3 mRNA was upregulated in all SLE B cell subsets relative to healthy controls but peaked in SLE DN2 cells. The gene was a significant DEG (≥2-fold change, FDR<0.05) between SLE and HC (see Scharer2019 - Epigenetic Programming in SLE B Cells, RNA-seq of 5 sorted B cell subsets, n=9 SLE + n=12 HC).
  • Validated at mRNA and protein levels: RT-qPCR confirmed ATF3 upregulation in resting naive B cells from an independent SLE cohort (P=0.025, n=15 HC, n=8 SLE). Intracellular flow cytometry showed significantly elevated ATF3 protein (MFI fold change over isotype) in SLE rN (P=0.034), aN (P=0.034), SM (P=0.033), and DN2 (P=0.048) relative to HC (Wilcoxon rank-sum test; n=5 HC, n=8 SLE) (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • 98 ATF3 target genes are disease DEGs: PageRank network analysis identified 98 ATF3 target genes among the SLE disease signature, of which 87% were upregulated in SLE. These target genes map to MTORC1 signalling, G2/M checkpoint, TNF signalling via NF-κB, hypoxia, UPR, apoptosis, and complement pathways (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • Highest chromatin accessibility at ATF3 motifs in SLE DN2: DNA footprinting analysis revealed the largest difference at ATF3 motifs between SLE and HC B cells, with SLE DN2 cells having the highest accessibility of any subset (P<0.05 vs. all other cell types). ATF3 ChIP-seq peaks significantly overlapped SLE-specific DARs (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • ATF3-Jun heterodimerization shifts equilibrium toward activation: Three Jun family members (JUN, JUNB, JUND) were enriched in the DN2 PageRank network and upregulated in SLE. Since ATF3 homodimers repress but ATF3-Jun heterodimers activate transcription, the coordinated upregulation suggests the equilibrium shifts toward activation specifically in SLE DN2 cells (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • ATF3 motifs did not co-occur with IRF4 at AICE composite elements: Only 7/98 (7%) ATF3 target genes were predicted to be regulated by IRF4, indicating ATF3 operates through a distinct regulatory network from the IRF4/BLIMP-1 PC differentiation programme (see Scharer2019 - Epigenetic Programming in SLE B Cells).
  • IFN-γ synergizes with TLR to enhance ATF3: The main T-BET inducer, IFN-γ, can synergize with TLR stimulation to enhance ATF3 expression — providing a mechanistic link between the T-BET-driven normal DN2 programme and the ATF3-driven SLE-amplified programme (see Scharer2019 - Epigenetic Programming in SLE B Cells, citing Ho et al. 2008).

Contradictions & Debates

None documented in current wiki sources.

DN2 B Cell, T-bet, EGR, TLR7, Extrafollicular Response, BLIMP-1, IRF4

Sources

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