Summary: New research reveals that repetitive DNA sequences long dismissed as “junk” perform essential regulatory roles in early human brain development. The study shows that LINE‑1 (L1) transposons—mobile elements within the non‑coding genome—are active in human pluripotent stem cells and help control key gene networks in the developing brain. When L1 activity was suppressed, lab-grown brain organoids developed abnormally, linking these elements to both evolutionary changes and disease-related pathways.
These findings highlight that much of the non‑coding genome contributes directly to neural development and may be central to understanding neurodevelopmental and neurodegenerative disorders, including links to conditions such as Parkinson’s disease and psychiatric illnesses.
Key Facts
- Hidden regulators: LINE‑1 transposons within non‑coding DNA act as regulatory elements that influence gene expression during brain formation.
- Consequences of silencing: Targeted suppression of L1 elements disrupted gene programs and reduced the size and organization of cerebral organoids.
- Disease connections: Many genes affected by L1 activity are associated with neurodevelopmental and psychiatric disorders, opening new directions for medical research.
Source: Lund University
For decades, large portions of the human genome were labeled “junk DNA” because they do not encode proteins. In fact only about 1.5% of the genome contains protein‑coding genes; the remaining sequence was often ignored. Recent work, however, increasingly shows that this non‑coding majority contains regulatory elements and mobile sequences that shape development, physiology, and evolution.
Researchers at Lund University, together with collaborators from Copenhagen, Cambridge, and New York University, focused on a family of transposable elements known as LINE‑1 (L1) retrotransposons. These “jumping genes” are abundant in the human genome and can be difficult to study because they are repetitive and mobile. The team combined induced pluripotent stem cells, cerebral organoids (miniature lab models of the developing brain), CRISPR interference (CRISPRi) to silence L1 activity, and high‑resolution sequencing to trace how individual L1 copies influence gene expression.
Contrary to the assumption that repetitive elements are inert, the study found thousands of hominoid‑specific L1 integrants are transcriptionally active in human stem cells and organoids. Activity varied by element and correlated with open, active chromatin states, indicating these sequences can function as cis‑regulatory units—modulating nearby gene transcription during early neural differentiation.
Repetitive DNA plays an active role in the developing brain
Using precise CRISPRi targeting, the researchers silenced sets of L1 promoters and monitored downstream effects. Silencing led to the loss of nearly one hundred chimeric transcripts derived from L1 sequences fused with nearby genes, altered neural differentiation programs, and smaller, structurally abnormal cerebral organoids. These results indicate that L1‑derived transcripts and promoter activity participate directly in the transcriptional networks that guide early human brain development.
From an evolutionary perspective, activity of hominoid‑specific L1 elements may have contributed to gene regulatory differences between humans and other primates. From a clinical perspective, the discovery that L1s regulate genes implicated in brain disorders suggests that changes in L1 activity could influence disease risk or progression.
Implications for brain disease research
The Lund team is extending this work through international collaborations, including contributions to the ASAP (Aligning Science Across Parkinson’s) Collaborative Research Network. Future studies will analyze patient‑derived cells and postmortem brain tissue to determine whether altered L1 activity is present in individuals with neurodevelopmental disorders or age‑related neurodegeneration such as Parkinson’s disease.
Lead investigator Johan Jakobsson emphasizes that these repetitive elements are not merely genomic fossils: they are active regulators that form part of the cellular machinery in developing neural tissue. Understanding where and when L1 elements act may reveal new molecular targets and biomarkers for neurodevelopmental and neuropsychiatric conditions, and eventually inform therapeutic strategies.
About this genetics, neurodevelopment, and neurology research news
Author: Anna Elizabeth Hellgren
Source: Lund University
Contact: Anna Elizabeth Hellgren – Lund University
Image: The image is credited to Neuroscience News
Original Research: Open access. “LINE‑1 retrotransposons mediate cis‑acting transcriptional control in human pluripotent stem cells and regulate early brain development” by Johan Jakobsson et al., Cell Genomics. DOI: 10.1016/j.xgen.2025.100979
Abstract
LINE‑1 retrotransposons mediate cis‑acting transcriptional control in human pluripotent stem cells and regulate early brain development
Long interspersed nuclear element 1 (L1) retrotransposons are a major source of genetic variation. Mechanistic studies of how L1s influence human developmental programs have been limited by the difficulty of profiling and manipulating specific L1 copies. This study demonstrates that thousands of hominoid‑specific L1 integrants are expressed in human induced pluripotent stem cells and cerebral organoids. Individual L1 promoter activity varies and correlates with active epigenetic marks. CRISPRi‑mediated silencing of L1s revealed nearly one hundred co‑opted L1‑derived chimeric transcripts; L1 suppression altered neural differentiation trajectories and reduced cerebral organoid size. Together, these data implicate L1s and L1‑derived transcripts in hominoid‑specific central nervous system developmental processes.