Estrogen Receptors Bind to and Activate the HOXC4/HoxC4 Promoter to Potentiate HoxC4-mediated Activation-induced Cytosine Deaminase Induction, Immunoglobulin Class Switch DNA Recombination, and Somatic Hypermutation

Mai, Thach; Zan, Hong; Zhang, Jin Song; Hawkins, J. Seth; Xu, Zhenming; Casali, Paolo

doi:10.1074/jbc.m110.169086

Cited by 76 publications

(80 citation statements)

References 81 publications

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“…Rearranged V 186.2 DJ H -Cγ1 cDNA encoding the anti-NP IgH chain was amplified using a V 186.2 leader-specific forward primer together with a reverse Cγ1-specific primer (13) and Phusion™ high fidelity DNA polymerase (New England BioLabs). PCR conditions were 98°C for 10 s, 60°C for 45 s and 72°C for 1 min for 30 cycles.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

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Pone

Lam

et al. 2014

The Journal of Immunology

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Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require AID, and plasma cell differentiation, which requires Blimp-1, are critical for the generation of class-switched and hypermutated (mature) antibody and autoantibody responses. We showed here that the histone deacetylase (HDAC) inhibitors (HDI) valproic acid (VPA) and butyrate upregulated miR-155, miR-181b and miR-361, which silenced AICDA/Aicda (AID) mRNA, and miR-23b, miR-30a and miR-125b, which silenced PRDM1/Prdm1 (Blimp-1) mRNA, in human and mouse B cells. This led to downregulation of AID, Blimp-1 and Xbp-1 expression, thereby dampening CSR, SHM and plasma cell differentiation without altering B cell viability or proliferation. The selectivity of HDI-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important inducers/modulators of AICDA/Aicda), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2 or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell intrinsic epigenetic mechanisms, VPA blunted class-switched and hypermutated T-dependent and T-independent antibody responses in C57BL/6 mice. In addition, it decreased class-switched and hypermutated autoantibodies, ameliorated disease and extended survival in lupus MRL/Faslpr/lpr mice. Our findings outline epigenetic mechanisms that modulate expression of an enzyme (AID) and transcription factors (Blimp-1 and Xbp-1) that critical to the B cell differentiation processes that underpin antibody and autoantibody responses. They also provide therapeutics proof-of-principle in autoantibody-mediated autoimmunity.

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Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Upregulate B Cell microRNAs That Silence AID and Blimp-1 Expression for Epigenetic Modulation of Antibody and Autoantibody Responses

White

Pone

Lam

et al. 2014

The Journal of Immunology

Self Cite

107

140

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“…The estrogen-mediated reduction of miR-146a results in increased LPS-induced IFN-γ and iNOS expression. Estrogen promotes AID expression that leads to increased antibody and autoantibody responses in females (76, 123). In addition to enhancing transcription of the Aicda gene by activating the promoter of HOXC4/HoxC4 , which is important for Aicda induction (76, 123, 124), estrogen can modulate AID expression by regulating miRNAs, specifically miRNA-155 and miRNA-181b, which target the 3′UTR of Aicda mRNA.…”

Section: Environmental and Hormonal Regulation Of Mirnas In Lupusmentioning

confidence: 99%

“…Estrogen promotes AID expression that leads to increased antibody and autoantibody responses in females (76, 123). In addition to enhancing transcription of the Aicda gene by activating the promoter of HOXC4/HoxC4 , which is important for Aicda induction (76, 123, 124), estrogen can modulate AID expression by regulating miRNAs, specifically miRNA-155 and miRNA-181b, which target the 3′UTR of Aicda mRNA. Estrogen-ERα has been shown to inhibit miRNA-155 and miRNA-181b expression in human breast cancer cells (125, 126).…”

Section: Environmental and Hormonal Regulation Of Mirnas In Lupusmentioning

confidence: 99%

MicroRNAs in lupus

2014

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies, which plays an important role in disease development and progression. Lupus preferentially affects women during their reproductive years. The pathogenesis of lupus is contributed by both genetic factors and epigenetic modifications that arise from exposure to the environment. Epigenetic marks, including DNA methylation, histone post-translational modifications and microRNAs (miRNAs), interact with genetic programs to regulate immune responses. Epigenetic modifications influence gene expression and modulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens or self-antigens, such as chromatin, histones and dsDNA in lupus. miRNAs play key roles in the post-transcriptional regulation of most gene-regulatory pathways and regulate both the innate and the adaptive immune responses. In mice, dysregulation of miRNAs leads to aberrant immune responses and development of systemic autoimmunity. Altered miRNA expression has been reported in human autoimmune diseases, including lupus. The dysregulation of miRNAs in lupus could be the result of multiple environmental factors, such as sex hormones and viral or bacterial infection. Modulation of miRNA is a potential therapeutic strategy for lupus.

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“…AID production is first controlled at the transcriptional level through a combination of enhancers and silencers which confine its transcription to activated B cells and limit its accumulation in germinal center B cells [40]. However, some activators of AID transcription such as HoxC4 and NF-kB can be physiologically activated outside the germinal center, through hormonal or inflammatory signals, leading to ectopic and/or supraphysiological expression [41][42][43][44]. Second, at the posttranscriptional level, at least two different miRNA modulate AID mRNA level (see the review by Papavasiliou and Ramiro in the same issue).…”

Section: Control Of Aid Dosage and Activitymentioning

confidence: 99%