Abstract
HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells. Here we show that HMGB4 and the highly similar rat Transition Protein 4 (HMGB4L1) are expressed in neuronal cells. Both proteins had slow mobility in nucleus of living NIH-3T3 cells. They interacted with histones and their differential expression in transformed cells of the nervous system altered the post-translational modification statuses of histones in vitro. Overexpression of HMGB4 in HEK 293T cells made cells more susceptible to cell death induced by topoisomerase inhibitors in an oncology drug screening array and altered variant composition of histone H3. HMGB4 regulated over 800 genes in HEK 293T cells with a p-value ≤0.013 (n = 3) in a microarray analysis and displayed strongest association with adhesion and histone H2A –processes. In neuronal and transformed cells HMGB4 regulated the expression of an oligodendrocyte marker gene PPP1R14a and other neuronal differentiation marker genes. In conclusion, our data suggests that HMGB4 is a factor that regulates chromatin and expression of neuronal differentiation markers.
Highlights
HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells
HMGB4 mRNA is undetectable during mouse embryonal development at the E10.5 stage but it is expressed in the brain and the pancreas at E12.5 and E14 stages, respectively[3,4,5]
HMGB4 shRNA-expressing cells expressed lower levels of HMGB4 and elevated levels of acetylated histones H2A and H4 (Fig. 3g). These results show that both HMGB1 and HMGB4 are associated with core histones and histone deacetylase (HDAC), and that HMGB4 and HMGB4L1 regulate post-translational modifications of histones in transformed cells derived from the central nervous system
Summary
HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells. We show that HMGB4 and the highly similar rat Transition Protein 4 (HMGB4L1) are expressed in neuronal cells. Both proteins had slow mobility in nucleus of living NIH-3T3 cells. Total RNA samples were isolated from adult mouse testes and analyzed via Northern Blot, using a probe derived from the entire coding sequence of mouse HMGB4. Total RNA samples were isolated from adult rat testes and from developing rat testes, and analyzed via Northern Blot, using a probe derived from the entire coding sequence of rat HMGB4L1. (e) Immunohistochemical staining of rat HMGB4L1 protein and in situ hybridization of mouse HMGB4 mRNA in adult testes. Neuronal cells from the hippocampus and the cerebellum were cultured, and both HMGB4 and HMGB4L1 expression (arrows) was detected with RT-PCR. Neuronal cells from the hippocampus and the cerebellum were cultured, and both HMGB4 and HMGB4L1 expression (arrows) was detected with RT-PCR. +RT =reverse transcribed, -RT =without reverse transcription
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