BloodJan 12, 2026

Genome-wide CRISPR screen identifies PTPA enzyme pathway linked to turning off fetal hemoglobin

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A genome-wide CRISPR strategy identified the PTPA-PP2A pathway as a regulator of fetal hemoglobin silencing in erythroid cells.

Evidence

This was a two-tier human coding-gene screening study using a CRISPR-Cas12a platform followed by a domain-focused CRISPR-Cas9 screen to test effects on HBG1/2 regulation and erythroid fitness.

Caveat

The evidence is from cellular genetic screens and rescue experiments, so therapeutic relevance for hemoglobinopathies remains to be tested beyond this system.

Simplified

Reactivating the fetal globin genes HBG1 and HBG2 in adult erythroid cells represents a validated therapeutic approach for hemoglobinopathies. Central mediators of the fetal-to-adult hemoglobin transition include the direct transcriptional HBG1/2 repressors BCL11A1,2, LRF3, and NFIA/X4. Limited-scale screens have attempted to expand the regulatory circuity surrounding fetal globin silencing, but systematic genome-wide dissection of such pathways is lacking. We employed a two-tiered genetic screening strategy - a novel CRISPR-Cas12a-based screening platform followed by a domain-focused CRISPR-Cas9 screen - to interrogate all known human coding genes for their impact on HBG1/2 regulation and erythroid cellular fitness, generating a comprehensive resource for the field. Among the top hits was PTPA, an activator of the serine-threonine phosphatase PP2A whose loss elevates HBG1/2 levels while preserving erythroid differentiation. Phenotypic rescue experiments revealed that PTPA silences HBG1/2 expression primarily by regulating BCL11A expression. To our knowledge, this study represents the most comprehensive CRISPR dissection of HBG regulation to date, highlighting the power of Cas12a-based genome-scale screening for uncovering disease-relevant pathways.

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Genome-wide CRISPR screen identifies PTPA enzyme pathway linked to turning off fetal hemoglobin

Abstract

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