Bromodomain Protein BRD4 Is Essential for Hair Cell Function and Survival

Kannan-Sundhari, Abhiraami; Abad, Clemer; Maloof, Marie E.; Ayad, Nagi G.; Young, Juan I.; Liu, Xue Zhong; Walz, Katherina

doi:10.3389/fcell.2020.576654

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…Recently, targeting Brd4 with inhibitors has received considerable attraction and is broadly applied to a wide spectrum of disease from ongoing clinical trial on cancer to cardiovascular disease (31,32,64). The prominent side-effect of Brd4 inhibition is memory loss in mice treated with pan-BRD inhibitor JQ1 and hearing loss in mice with specific deletion of Brd4 in hair cells so far (65,66). However, our study established a FIGURE 8 | Schematics showing that Brd4 regulates CD8 + T cell homeostasis and proliferation through controlling glucose metabolism.…”

Section: Brd4 Inhibition Dampens Cd8 + T Cell-mediated Adaptive Immunity During Acute Viral Infectionmentioning

confidence: 75%

Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

Peng

Zhang

et al. 2021

Front. Immunol.

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CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.

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Section: Brd4 Inhibition Dampens Cd8 + T Cell-mediated Adaptive Immunity During Acute Viral Infectionmentioning

confidence: 75%

Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

Peng

Zhang

et al. 2021

Front. Immunol.

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“…Brd4 gene mutation may be associated with craniofacial malformations and auricle malformations 18 . Brd4 can also affect the development of the inner ear of mice, such as the absence of Brd4 in the inner ear of mice can lead to severe postnatal hearing loss 19…”

Section: Discussionmentioning

confidence: 99%

Prkra Mutation Alters mRNA Expression During Embryonic External Ear Development

Liu

Lin

Yang

et al. 2023

Journal of Craniofacial Surgery

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To understand the changes in mRNA expression during the embryonic development of the external mouse ear after the point mutation of the Prkra gene, Prkra short ear mouse model was used to study the development of the embryonic external ear. The tissues of the embryonic external ear were obtained when mouse embryos developed to E15.5 and E17.5. The changes in the mRNA expression profile were detected and analyzed. Find_circ and CIRI2 softwares were used to identify the upregulated and down-regulated expression of mRNA in the experimental and control groups. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were conducted on the differentially expressed mRNA, and the related signal pathways were analyzed after the upregulation and down-regulation of mRNA expression. This study aimed to understand the regulation of mRNA expression in Prkra short-ear mice during the external ear development in embryos. The results showed a correlation between abnormally expressed mRNA and signal pathways and the regulation of the development of the external ear of Prkra short-ear mice, and there were differences in some key regulatory mRNA changes after the Prkra gene point mutation. This study will provide a new clue for the mechanism of mRNA regulating the development of the external mouse ear. The change in mRNA expression profile can also provide clues for studying the biological regulation mechanism of external ear embryonic development.

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“…The basic helix-loop-helix (bHLH) transcription factor Atoh1 is expressed in hair cells and has been shown to play a critical role in their fate determination and differentiation (Bermingham et al, 1999). Thus, we used an Atoh1-cre line that has been shown by several studies to drive Cre expression within inner ear hair cells (Supplementary Figure 1; Matei et al, 2005;Perrin et al, 2010Perrin et al, , 2013Ueyama et al, 2014;Tarchini et al, 2016;Kannan-Sundhari et al, 2020) to conditionally delete Fzd3 (Supplementary Figure 1). Although we found variability in Atoh1-cre driving tdTomato expression in supporting cells, all samples expressed tdTomato within hair cells and there was no evidence of tdTomato in inner ear afferents.…”

Section: Central Tonotopic Organization Of Spiral Ganglion Neurons Is Unaffected By Loss Of Fzd3 Within Peripheral Hair Cellsmentioning

confidence: 99%

Fzd3 Expression Within Inner Ear Afferent Neurons Is Necessary for Central Pathfinding

et al. 2022

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During development the afferent neurons of the inner ear make precise wiring decisions in the hindbrain reflective of their topographic distribution in the periphery. This is critical for the formation of sensory maps capable of faithfully processing both auditory and vestibular input. Disorganized central projections of inner ear afferents in Fzd3 null mice indicate Wnt/PCP signaling is involved in this process and ear transplantation in Xenopus indicates that Fzd3 is necessary in the ear but not the hindbrain for proper afferent navigation. However, it remains unclear in which cell type of the inner ear Fzd3 expression is influencing the guidance of inner ear afferents to their proper synaptic targets in the hindbrain. We utilized Atoh1-cre and Neurod1-cre mouse lines to conditionally knockout Fzd3 within the mechanosensory hair cells of the organ of Corti and within the inner ear afferents, respectively. Following conditional deletion of Fzd3 within the hair cells, the central topographic distribution of inner ear afferents was maintained with no gross morphological defects. In contrast, conditional deletion of Fzd3 within inner ear afferents leads to central pathfinding defects of both cochlear and vestibular afferents. Here, we show that Fzd3 is acting in a cell autonomous manner within inner ear afferents to regulate central pathfinding within the hindbrain.

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Bromodomain Protein BRD4 Is Essential for Hair Cell Function and Survival

Cited by 5 publications

References 39 publications

Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

Prkra Mutation Alters mRNA Expression During Embryonic External Ear Development

Fzd3 Expression Within Inner Ear Afferent Neurons Is Necessary for Central Pathfinding

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