Smarca4 (Brg1) is a haploinsufficient B-cell tumor suppressor that fine-tunes centrocyte cell fate decisions [smarca4_rna]. Smarca4 (Brg1) is a haploinsufficient B-cell tumor suppressor that fine-tunes centrocyte cell fate decisions [smarca4_rna]

SMARCA4 encodes one of two mutually-exclusive ATPase subunits in the Brg/Brm associated factor (BAF) complex that is recruited by transcription factors to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ~30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperates with Myc over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of transcription factors that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family and NFκB. Loss of activity for these factors phenocopied aberrant Bcl6 activity within murine centrocytes and human BL cells. Smarca4 therefore facilitates chromatin accessibility for transcription factors that shape centrocyte trajectories, and loss of fine-control of these programs biases towards centroblast cell-fate and GC hyperplasia. Overall design: Compararive gene expression profiling analysis using WT or Smarca4 HET knockout in mouse GC B-cell

SMARCA4基因编码Brg/Brm相关因子（Brg/Brm associated factor, BAF）复合体中两种互斥的ATP酶亚基之一，该复合体可被转录因子招募，以驱动染色质可及性与转录激活。SMARCA4是人类癌症中最常发生复发性突变的基因之一，在约30%的生发中心（germinal center, GC）源性伯基特淋巴瘤（Burkitt lymphomas）中存在该基因突变。在小鼠模型中，生发中心特异性Smarca4单倍体不足可与Myc过表达协同促进淋巴瘤发生。进一步研究发现，单等位基因Smarca4缺失可通过显著提高中心细胞（centrocyte）向暗区（dark zone）的再循环速率，诱导生发中心增生并伴随中心母细胞（centroblast）极化。从机制层面而言，Smarca4缺失会降低在中心细胞中激活的、参与驱动生发中心退出的转录因子的活性，包括SPI1（PU.1）、IRF家族及NFκB。这些转录因子的活性缺失，可在小鼠中心细胞与人类伯基特淋巴瘤细胞中模拟异常的Bcl6活性。因此，Smarca4可协助调控塑造中心细胞命运轨迹的转录因子的染色质可及性；而对这些基因程序的精细调控缺失，则会使细胞偏向中心母细胞命运，进而引发生发中心增生。整体实验设计：本研究采用野生型（wild type, WT）或Smarca4杂合敲除（heterozygous, HET）的小鼠生发中心B细胞，进行比较基因表达谱分析。