HERF1, a Novel Hematopoiesis-Specific RING Finger Protein, Is Required for Terminal Differentiation of Erythroid Cells

Abstract

The AML1/core binding factor ␤ (CBF␤) transcription factor is essential for definitive hematopoiesis; however, the downstream pathways through which it functions remain incompletely defined. Using a differential cloning approach to define components of this pathway, we have identified a novel gene designated HERF1 (for hematopoietic RING finger 1), whose expression during development is dependent on the presence of functional AML1/CBF␤. HERF1 contains a tripartite RING finger-B box-␣-helical coiled-coil domain and a C-terminal region homologous to the ret proto-oncogene-encoded finger protein. Expression of HERF1 during embryogenesis coincides with the appearance of definitive erythropoiesis and in adult mice is restricted to erythroid cells, increasing 30-fold during terminal differentiation. Importantly, inhibition of HERF1 expression blocked terminal erythroid differentiation of the murine erythroleukemia cell line MEL, whereas its overexpression induced erythroid maturation. These results suggest an important role for this protein in erythropoiesis.

Downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival

“…It has been shown that TRIM10/HERF1 expression increases dramatically in MEL cells following treatment with DMSO [1]. To determine if this enhanced expression is a direct effect of DMSO or the result of an erythroid differentiation program activated by a differentiation inducer, we measured the change in TRIM10/HERF1 steady-state mRNA expression levels in two different spleen-focus forming virus (SFFV)-MEL cell lines following treatment with either of the chemical inducers (DMSO or hexamethylene bisacetamide (HMBA)) or the physiological inducer erythropoietin (EPO) ( Figure 1A).…”

“…Knowing that TRIM10/HERF1 upregulation during terminal erythroid differentiation induces globin gene expression [1], we aimed to determine if TRIM10/HERF1 expression also modulates the erythroid splicing of exon 16. MEL cell clones stably transfected with a tetracycline (Tet)-inducible vector expressing sense TRIM10/HERF1 RNA (HERF(+) cells) were tested for their ability to regulate exon 16 splicing.…”

“…Harada and colleagues [1] have shown that TRIM10/HERF1 increase is required for terminal differentiation of erythroid cells based on their ability to produce hemoglobin. Here, we demonstrated that this factor is also crucial for another late erythroid-specific event, the regulated splicing of exon 16 on 4.1R pre-mRNA.…”

“…Hematopoietic RING finger 1 (HERF1) was originally described as a downstream component of a regulatory cascade initiated by AML1/core binding factor (CBFβ) [1], a transcription factor complex essential for the formation of the definitive hematopoietic system [2,3]. Additionally, HERF1 was independently identified by a comprehensive genomics approach as TRIM10, a member of the N-terminal RING finger/B-box/coiled coil (RBCC) or tripartite motif (TRIM) family of proteins ( [4][5][6] and references therein).…”

“…Conversely, inhibition of TRIM10/HERF1 expression blocks hemoglobin production in MEL cells, even in the presence of DMSO, suggesting that TRIM10/HERF1 must play a key role in definitive erythroid development [1]. Insertion of the Friend viral genome upstream of the Spi-1/PU.1 locus in MEL cells leads to constitutive upregulation of the Spi-1/PU.1 gene, uncontrolled proliferation, and a subsequent block in the differentiation of the affected erythroblasts [8,9].…”