AFF4

AFF4 Full Name

AF4/FMR2 family, member 4

AFF4 Introduction

AF4/FMR2 Family Member 4 (AFF4), also known as AF4-Related Gene 4 or AF5q31, is a highly conserved transcriptional coactivator belonging to the AF4/FMR2 (AFF) family, which plays a pivotal role in regulating gene transcription and RNA polymerase II (Pol II)-mediated elongation. Distinguished from other AFF family members, AFF4 is a core component of the Super Elongation Complex (SEC), a multi-protein assembly that enhances the elongation phase of transcription— a critical step in the expression of genes involved in cell growth, differentiation, and development. AFF4 is widely expressed across mammalian tissues, with prominent expression in the brain, hematopoietic cells, and embryonic tissues, where it modulates the transcription of key developmental and hematopoietic genes. By facilitating transcriptional elongation, AFF4 ensures the timely and efficient expression of genes essential for cellular homeostasis and organismal development. Today, AFF4 is recognized not only as a key transcriptional coactivator but also as a critical regulator of gene expression, with profound implications for developmental biology, hematology, and cancer research.

Figure 1. Schematic structure of AFF4.

Tissue Distribution and Subcellular Localization
AFF4 is expressed in all human tissues examined, but its abundance varies considerably across cell types and developmental stages. The highest expression is found in lymphoid tissues (thymus, spleen, lymph nodes) and the testis, reflecting the importance of AFF4 in cell proliferation and differentiation in these compartments. Moderate expression is detected in the brain (particularly in the cerebral cortex, hippocampus, and cerebellum), lung, kidney, and placenta, while lower expression is found in the liver, heart, and skeletal muscle. During embryonic development, AFF4 expression is higher than in adult tissues, consistent with its role in regulating genes involved in cell fate specification and organogenesis. At the subcellular level, AFF4 is exclusively nuclear and concentrates in specific nuclear bodies known as SEC foci or transcription factories. These foci are dynamic structures that form in response to transcriptional activation signals, and their number and size correlate with the level of ongoing transcription. AFF4 contains a bipartite nuclear localization signal (NLS) within its N-terminal region (residues 180-210) that is necessary and sufficient for nuclear import; deletion or mutation of this NLS results in cytoplasmic retention and loss of SEC assembly. In addition to its localization in nuclear foci, AFF4 also associates with chromatin, as demonstrated by chromatin immunoprecipitation (ChIP) experiments, and its chromatin binding is enhanced by treatment with transcriptional activators such as phorbol esters or by recruitment of P-TEFb.

Role in Inflammation and Immune Responses
AFF4 plays a critical role in the transcriptional activation of pro-inflammatory and immune response genes, many of which are characterized by promoter-proximal Pol II pausing that is released by the SEC. Toll-like receptor (TLR) signaling in macrophages and dendritic cells induces the rapid expression of cytokines such as TNFα, IL-6, IL-1β, and chemokines such as CXCL10 and CCL2. This rapid induction requires SEC-mediated pause release, and AFF4 is recruited to these genes following TLR stimulation. Knockdown of AFF4 in macrophages impairs the induction of inflammatory cytokines and reduces the inflammatory response in animal models of endotoxemia and septic shock. Similarly, in T lymphocytes, AFF4 is required for the expression of effector cytokines (IFNγ, IL-17, IL-22) following T cell receptor (TCR) activation, and AFF4-deficient T cells show impaired proliferation and differentiation. The role of AFF4 in inflammation extends to chronic inflammatory diseases: in rheumatoid arthritis, AFF4 expression is elevated in synovial fibroblasts and infiltrating immune cells, and AFF4 knockdown reduces the production of pro-inflammatory mediators in these cells.

Alternate Names for AFF4

AFF4; AF4/FMR2 family, member 4; AF4/FMR2 family member 4; Laf4l;

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