Table I.

BCL6 expression in human pre-eclamptic placentas.

Reference	Sample number/patient information	Method/dataset/GEO	Main results
Enquobahrie et al. (2008)	n = 18 controls (38.9 wk, 5.6% preterm delivery <37 wk and 38.9% CS, 72.2% labor). n = 18 PE (35.8 wk, 50% preterm delivery and 55.6% CS, 66.7% labor).	Microarray (Operon’s Human Genome Array Ready Oligo Set™ version 2.1) and qPCR.	58 genes (56 up- and 2 downregulated) were differentially expressed in PE placentas, including upregulated BCL6, with a fold change of 1.78 (P = 0.0154).
Winn et al. (2009)	n = 11 preterm labor with no evidence of infection (30.2 ± 7.1 wk, range 24–36, 18% CS and 100% labor). n = 12 severe PE (30.7 ± 9.1 wk, range 24–36, 50% CS and 83% labor).	Microarray platform high-density HG-U133A and HGU133B GeneChips (Affymetrix, Santa Clara, CA); GEO accession number: GSE14722.	55 genes were differentially expressed in PE placentas, including upregulated BCL6, with a fold change of 1.69.
Sitras et al. (2009)	n = 21 controls (277 ± 9 days, 38% CS). n = 16 severe PE (238 ± 25 days, 69% CS).	30 K Human Genome Survey Microarray v.2.0 (Applied Biosystems); GEO accession number: GSE10588.	213 genes were significantly upregulated in severe PE placentas, including BCL6, with a fold change of 2.2 (P = 0.01). 82 genes were downregulated. 168 genes were differentially expressed between EO- versus LO-PE placentas, suggesting differences in pathophysiology.
Nishizawa et al. (2011)	n = 8 controls (38.1 ± 0.8 wk). n = 8 FGR (37.3 ± 1.0 wk). n = 8 severe PE (34.4 ± 1.8 wk), all CS.	Microarray experiments with Affymetrix GeneChip system (Affymetrix, Santa Clara, CA, USA). GEO accession number: GSE24129.	62 genes were differentially expressed in both PE and FGR. TP53-downstream apoptosis-related genes, such as BCL6 and BAX, were found to be more highly upregulated in PE- than in FGR placentas. BCL6 was upregulated in PE placentas with a fold change of 2.02 (P = 0.0024).
Xiang et al. (2013)	n = 22 (5 for microarray) uncomplicated pregnancies (39.38 ± 1.19 wk), CS. n = 23 (7 for microarray) PE (35.34 ± 3.07 wk), CS.	Microarray experiments with Roche Nimblegen Gene Expression 126135 K Arrays. GEO accession number: GSE43942.	1312 genes were differentially expressed in PE placentas, including upregulated BCL6 (fold change 2.51, P = 0.0026; Supplementary Table S2).
Trifonova et al. (2014)	n = 11 physiological pregnancies (40 ± 2 wk, 0% premature birth). n = 10 PE (38 ± 1 wk, 50% premature birth), 6 moderate PE and 4 severe PE.	HT-12 BeadChip microarrays (Illumina, USA).	63 genes were differentially expressed in PE placentas (50 up- and 13 downregulated). BCL6 was upregulated with a fold change of 2.36 (P = 0.0006).
Louwen et al. (2014)	n = 7 controls (37.6 ± 0.7 wk, 4 with CS, 2 with eCS, 1 with opVD). n = 7 PE (37.1 ± 0.5 wk; 5× CS, 1× eCS with labor, 1× opVD).	Self-designed TaqMan gene array, Applied Biosystems (Darmstadt, Germany); qPCR verification.	BCL6 gene was upregulated in LO-PE with a fold change of 1.47 (P = 0.087). Increased BCL6 may be involved in deregulated cell cycle regulation, survival, and differentiation processes of villous trophoblasts in pre-eclamptic placentas.
Sober et al. (2015)	n = 4 LO-PE with IUGR. n = 4 LO-PE without IUGR (266.1 ± 3.94 days, delivery mode VD/CS: 2/6).	Library preparation with Nextera™ Technology (Illumina) total RNA sequencing was performed on Illumina HiSeq2000.	199 and 98 genes were differentially expressed in PE without IUGR and PE with IUGR, respectively. BCL6 was in the top-gene list and upregulated in LO-PE with IUGR (log2 fold change 0.77, P = 0.00081, Supplementary Data S3).
Than et al. (2018)	n = 5 preterm control (31.0 wk, range 30.9–34.0), CS. n = 12 preterm severe PE with and without HELLP (31.2 wk, range 29.3–33.2), CS.	Whole-Human Genome Oligo Microarray G4112A (Agilent Technologies, Santa Clara, CA); GEO accession numbers GSE65866, GSE65940, and GSE66273.	BCL6 upregulation sensitized trophoblasts to ischemia and repressed differentiation (log fold change 1.86, absolute fold change 3.64, P = 0.00065; Supplementary Data S1). BCL6 was highly expressed in preterm but not in term PE placentas, suggesting its potential role only in the pathology of preterm cases.
Guo et al. (2021)	n = 20 from 7 controls delivered preterm (n = 7, <34 wk) or at term (n = 13, >36 wk). n = 24 PE including EO (n = 8, <34 wk), severe LO (n = 4, >36 wk) and non-severe LO (n = 12; >36 wk).	The study performed a deeply re-analyzing of publicly available datasets (Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Feature Number version)).	1016 genes were differentially expressed in severe EO-PE. Severe LO-PE showed a deregulation of 133 genes. The comparison between EO-PE versus LO-PE identified 226 differentially expressed genes. BCL6 was upregulated only in EO-PE with a log fold change of 1.603 (P = 0.00026).
Ren et al. (2021)	n = 32 from 30 controls including twins (273.90 ± 8.45 days). n = 33 PE including twins (n = 9 for EO severe PE, 216.80 ± 15.20 days; n = 15 (14) for severe LO-PE, 260.60 ± 13.87 days; n = 9 (7) for LO mild PE, 266.10 ± 10.09 days).	TruSeq RNA Kit (Illumina) followed by paired-end sequencing using Illumina Hiseq 2500.	2977 genes, which are enriched with metabolism-related pathways and transporter functions, were differentially expressed in severe EO-PE, whereas 375 genes, which are enriched with immune-related pathways, were differentially expressed in severe LO-PE. BCL6 was upregulated in both EO- and LO-PE (log2 fold change 0.85, P = 1.51E−06; Supplementary Table S3).

BCL6, B-cell lymphoma 6; CS, cesarean section; eCS, emergency cesarean section after the onset of labor; EO-PE, early-onset pre-eclampsia; FGR, fetal growth restriction; GEO, Gene Expression Omnibus; HELLP, Hemolysis, Elevated Liver enzymes and Low Platelets; IUGR, intrauterine growth restriction; LO-PE, late-onset pre-eclampsia; opVD, operative vaginal delivery; PE, pre-eclampsia; VD, vaginal delivery; wk, week.