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Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a genome-wide co-expression analysis.

Code ↔ Paper

13 matches between paragraphs of the paper and lines of its authors' code, computed by the harvester (lexical-v1). Click a colored paragraph or line to see its counterpart.

The 13 matches
  1. [1] § Materials and methods › Replication and sensitivity analyses ↔ 02_genomewide_screen.py, lines 17–86 · score 0.81 · Cross region rank, Spearman rank correlation, genome wide screen, nucleus accumbens, hippocampus, putamen
  2. [2] § Materials and methods › Co-expression and enrichment analysis ↔ 02_genomewide_screen.py, lines 1–15 · score 0.76 · genome wide co, brain expressed gene, nucleus accumbens, PCDH coordination score, hippocampus, putamen
  3. [3] § Materials and methods › Methylation-level analysis ↔ 07_methylation_analysis.py, lines 16–44 · score 0.72 · probes mapping, DNMT genes, pairwise correlations, methylation, GSE131706, PCDH
  4. [4] § Materials and methods › Confound adjustment ↔ 08_sensitivity_analyses.py, lines 24–147 · score 0.65 · GTEx subject, PCDH coordination score, regressing, age, sex, residualize
  5. [5] § Materials and methods › Co-expression and enrichment analysis ↔ utils.py, lines 161–195 · score 0.64 · Odds ratios, Enrichment statistics, PCDH coordinated genes, epigenetic regulator, threshold, scores
  6. [6] § Results › Genome-wide screen identifies epigenetic regulators as top PCDH-coordinated genes in BA9 ↔ 02_genomewide_screen.py, lines 1–15 · score 0.62 · genome wide co, brain expressed genes, PCDH coordination scores, epigenetic regulators, BA9, ranked
  7. [7] § Results › Protocadherin co-expression is a consistent feature of human brain regions ↔ 06_tissue_enrichment.py, lines 15–71 · score 0.62 · blood ratio, tissue enrichment, PCDH co expression, grand, Pearson, GTEx
  8. [8] § Results › Multi-region replication of enrichment ↔ 02_genomewide_screen.py, lines 17–86 · score 0.61 · nucleus accumbens, Epigenetic gene rankings, genome wide, hippocampus, putamen, Spearman
  9. [9] § Results › Cross-dataset replication and preservation across conditions ↔ 07_methylation_analysis.py, lines 16–44 · score 0.58 · probes mapping, DNMT genes, Methylation, GSE131706, clustered, protocadherin
  10. [10] § Materials and methods › Replication and sensitivity analyses ↔ 05_condition_comparisons.py, lines 1–13 · score 0.56 · bipolar disorder, PCDH co expression, schizophrenia, psychiatric, GSE80655
  11. [11] § Materials and methods › Confound adjustment ↔ 03_celltype_deconvolution.py, lines 1–13 · score 0.55 · PCDH coordination score, partial correlation, recomputation, deconvolution, NNLS, Cell
  12. [12] § Results › Cross-dataset replication and preservation across conditions ↔ utils.py, lines 31–46 · score 0.52 · anterior cingulate, frontal cortex, nucleus accumbens
  13. [13] § Results › Robustness to cell-type composition and donor covariates ↔ 08_sensitivity_analyses.py, lines 1–22 · score 0.50 · donor age, sex, Adjustment, covariation, RNA, enrichment

Paper

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The authors' code

Python · 90 lines · 3.5 KB · MIT · 4 matches

  1. """
  2. 02_genomewide_screen.py
  3. Genome-wide co-expression screen and epigenetic regulator enrichment (Table 2, Figure 1).
  5. Ranks all brain-expressed genes by PCDH coordination score in GTEx BA9.
  6. Tests enrichment of epigenetic regulators in top 5%.
  7. Replicates in putamen, hippocampus, and nucleus accumbens.
  9. Harbert D. (2026) BMC Genomics
  10. """
  12. import sys, os
  13. sys.path.insert(0, os.path.dirname(__file__))
  14. from utils import *
  15. import matplotlib.pyplot as plt
  17. def main():
  18. ensure_dirs()
  19. cache_dir = os.path.join(os.path.dirname(RESULTS_DIR), 'cache')
  20. os.makedirs(cache_dir, exist_ok=True)
  22. tpm_path = download_if_needed(GTEX_TPM_URL, os.path.join(cache_dir, 'GTEx_gene_tpm.gct.gz'))
  23. annot_path = download_if_needed(GTEX_SAMPLE_URL, os.path.join(cache_dir, 'GTEx_SampleAttributes.txt'))
  25. gene_lists = load_gene_lists()
  26. pcdh_all = gene_lists['pcdh_all']
  27. epigen = gene_lists['epigenetic']
  29. # Primary analysis: BA9
  30. test_regions = {
  31. 'BA9': BRAIN_REGIONS['BA9'],
  32. 'Putamen': BRAIN_REGIONS['Putamen'],
  33. 'Hippocampus': BRAIN_REGIONS['Hippocampus'],
  34. 'Nucleus_accumbens': BRAIN_REGIONS['Nucleus_accumbens'],
  35. }
  37. all_enrichment = []
  38. all_scores = {}
  40. for region_key, region_smtsd in test_regions.items():
  41. print(f"\n{'='*60}")
  42. print(f"Genome-wide screen: {region_key}")
  43. print(f"{'='*60}")
  45. expr, _ = load_gtex_region(tpm_path, annot_path, region_smtsd, min_tpm=1.0)
  47. scores = compute_pcdh_coordination_scores(expr, pcdh_all)
  48. enrichment = fisher_enrichment_test(scores, epigen)
  49. enrichment['region'] = region_key
  51. all_enrichment.append(enrichment)
  52. all_scores[region_key] = scores
  54. print(f"\n ENRICHMENT: {enrichment['fold_enrichment']}x")
  55. print(f" {enrichment['n_epigen_in_top']}/{enrichment['n_epigen_tested']} in top 5%")
  56. print(f" OR = {enrichment['odds_ratio']}, p = {enrichment['p_value']:.2e}")
  58. if enrichment['epigen_in_top']:
  59. print(f"\n Top epigenetic regulators:")
  60. for g in enrichment['epigen_in_top']:
  61. row = scores[scores['gene'] == g].iloc[0]
  62. print(f" {g:12s} rank {int(row['rank']):>5d}, r = {row['pcdh_score']:+.4f}")
  64. scores.to_csv(os.path.join(RESULTS_DIR, f'genomewide_rankings_{region_key}.csv'), index=False)
  65. del expr
  67. # Cross-region rank correlations
  68. print(f"\n{'='*60}")
  69. print("Cross-region Spearman rank correlations of epigenetic gene rankings:")
  70. regions = list(all_scores.keys())
  71. for i in range(len(regions)):
  72. for j in range(i+1, len(regions)):
  73. r1, r2 = regions[i], regions[j]
  74. merged = all_scores[r1][['gene','rank']].merge(
  75. all_scores[r2][['gene','rank']], on='gene', suffixes=(f'_{r1}', f'_{r2}'))
  76. epig_m = merged[merged['gene'].isin(epigen)]
  77. if len(epig_m) > 2:
  78. rho, p = spearmanr(epig_m[f'rank_{r1}'], epig_m[f'rank_{r2}'])
  79. print(f" {r1} vs {r2}: rho = {rho:.3f}, p = {p:.2e}")
  81. # Save enrichment summary
  82. summary = pd.DataFrame([{k: v for k, v in e.items() if k != 'epigen_in_top' and k != 'contingency_table'}
  83. for e in all_enrichment])
  84. summary.to_csv(os.path.join(RESULTS_DIR, 'table2_enrichment_all_regions.csv'), index=False)
  86. print(f"\nResults saved to {RESULTS_DIR}/")
  89. if __name__ == '__main__':
  90. main()

02_genomewide_screen.py at commit 510c8c7, under MIT · at the source

Overview

Authors: Drake H. Harbert1
  1. Inner Architecture LLC, Canton, OH, United States
Journal: Frontiers in genetics, volume 17, article 1807347
Dates: received 9 February 2026; accepted 12 May 2026; published online 9 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3389/fgene.2026.1807347 · PMID 42488351 · PMCID PMC13391046 · OpenAlex W7167711804
Open access: gold, a free copy (OpenAlex)
Status: code verified
Categories: genetics / omics (modality), human (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Connectivity
Keywords: cell-type deconvolution, chromatin remodeling, co-expression, epigenetic regulation, GTEx, human brain, neurodevelopmental disorders, protocadherin
Topic: Epigenetics and DNA Methylation (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Citations: not cited yet (Europe PMC); 40 references in the paper

Abstract

How does the brain build and maintain the precise wiring patterns that distinguish one neuron from another? Clustered protocadherins (PCDHs)—a family of cell-surface molecules that give each neuron a unique identity tag—are central to this process. Their expression is famously controlled by an elaborate locus-specific epigenetic system involving DNA methylation, CTCF binding, and chromatin looping. Whether the activity of the broader epigenetic regulatory machinery is coordinated with protocadherin expression across the human brain has not been systematically tested. Here we show that epigenetic regulators are preferentially co-expressed with protocadherins across multiple human brain regions, suggesting a broader transcriptional coordination than the locus-specific mechanisms previously characterized. Using GTEx v8 RNA-seq data from 2,642 brain samples across 13 regions, we conducted a genome-wide co-expression screen and observed a 6.5‐fold enrichment of epigenetic regulators in the top 5% of PCDH-coordinated genes in prefrontal cortex (Fisher’s exact p = 2.8 × 10−10). The enrichment replicated independently across additional brain regions, persisted under multiple sensitivity analyses, was preserved after adjustment for cell-type composition, and replicated in an independent brain-bank cohort. The top-ranked epigenetic regulators converge on a defined set of chromatin-remodeling genes implicated in well-characterized neurodevelopmental syndromes. These findings reframe protocadherin biology by extending its epigenetically coordinated context beyond the locus itself to a broader transcriptional program shared with the chromatin-remodeling machinery associated with neurodevelopmental disease. The conceptual advance is consistent with—though does not by itself establish—direct co-regulation, and identifies a specific set of testable mechanistic hypotheses for how disrupted chromatin-remodeling activity in neurodevelopmental disorders may propagate to PCDH-dependent neuronal identity programs in the human brain.

Reproduced under the paper's license (CC BY), from the paper cited above.

Repository

Its files are read in the Code ↔ Paper reader above, with 13 matches between paragraphs and lines of code.

nwharbert8-ui/epigenetic-pcdh-coordination

License: MIT
State: the link answers, verified on 27 September 2026
Evidence: files inventoried
Commit: 510c8c7463d3f84723d22aea57178a43464d2774, 9 February 2026
Languages: Python (10)
Size: 16 files, 10 scripts
Software Heritage: not archived
Found in: the text, “Analytical parameters and software”
Holds: README, license file, environment (requirements.txt)
Not found: CITATION.cff, tests, continuous integration, documentation
Tools: Matplotlib (1 file), NumPy (1 file), pandas (1 file), SciPy (1 file), statsmodels (1 file)
Availability: 1 check, the latest on 27 September 2026: the link answers
  • 27 September 2026: the link answers
12 files
At the source: github.com/nwharbert8-ui/epigenetic-pcdh-coordination

The paper's code and data availability statement is in the Data section.

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  • 10 scripts, each with its path and the digest of its content;
  • 13 matches between paragraphs of the paper and lines of the code (method lexical-v1);
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Data

Datasets cited

Data availability statement

The original contributions presented in the study are publicly available. These data can be found in the GTEx v8 repository under dbGaP accession number phs000424.v8.p2 (https://gtexportal.org), and in the NCBI Gene Expression Omnibus (GEO) repository under accession numbers GSE80655 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE80655) and GSE131706 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE131706). Analysis code and intermediate results are publicly available in the GitHub repository at https://github.com/nwharbert8-ui/epigenetic-pcdh-coordination.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 1 author, 8 keywords, 39 references.

Cite

This paper

Harbert, D. H. (2026). Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a genome-wide co-expression analysis. Frontiers in genetics, 17, 1807347. https://doi.org/10.3389/fgene.2026.1807347

BibTeX

@article{harbert2026epigenetic,
author = {Harbert, Drake H.},
title = {{Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a genome-wide co-expression analysis}},
journal = {Frontiers in genetics},
year = {2026},
month = jul,
volume = {17},
pages = {1807347},
publisher = {Frontiers Media SA},
issn = {1664-8021},
doi = {10.3389/fgene.2026.1807347},
url = {https://doi.org/10.3389/fgene.2026.1807347},
pmid = {42488351},
pmcid = {PMC13391046}
}

RIS

TY - JOUR
AU - Harbert, Drake H.
TI - Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a genome-wide co-expression analysis
T2 - Frontiers in genetics
J2 - Front Genet
PY - 2026
DA - 2026/07/09
VL - 17
SP - 1807347
SN - 1664-8021
PB - Frontiers Media SA
DO - 10.3389/fgene.2026.1807347
UR - https://doi.org/10.3389/fgene.2026.1807347
LA - en
ER -

CSL-JSON

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"given": "Drake H."
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"page": "1807347",
"DOI": "10.3389/fgene.2026.1807347",
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"ISSN": "1664-8021",
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