About

Laura Landweber, PhD, is a Professor of Biochemistry and Molecular Biophysics, Biological Sciences, and Systems Biology at Columbia University. Her research investigates the origin of novel genetic systems and complex genome architectures, using the ciliate Oxytricha as a model. Her work focuses on microbial eukaryotes with complex genome structures, employing functional genomic experiments that manipulate chromosome structure to study the roles of RNA in mediating epigenetic inheritance and genome programming, as well as comparative genomic analysis to examine the evolution of scrambled genome organization. She has contributed significantly to understanding how genome reorganization occurs during development, including the role of small and long non-coding RNAs in programming genome organization across generations, bypassing the information encoded in DNA.

Research topics

• Biology
• Genetics
• Evolutionary biology
• Computational biology

Selected publications

• A PIWI protein-dependent DNA N6-adenine methylation pathway in <i>Oxytricha</i> protects genomic sequences from deletion

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-07

  articleOpen accessSenior authorCorresponding

  The ciliate Oxytricha undergoes massive genome rearrangements during development to produce a functional nucleus from an encrypted zygotic genome. PIWI-interacting small RNAs protect DNA regions against deletion, but how that protective mark is established has been a mystery. Recently our lab discovered MTA1, a methyltransferase that catalyzes DNA N6-adenine (6mA) methylation. Both MTA1 and the Oxytricha Piwi protein, Otiwi1, are required for development, and Otiwi1 mutation eliminates 6mA signal. To examine the role of 6mA, we analyzed its genome-wide distribution across development in wild-type and MTA1 mutant backcrossed cells. We find specific and abundant enrichment on retained sequences, suggesting a protective role for this epigenetic mark. Furthermore, programmed retention of a DNA region that is normally deleted leads to accumulation of new 6mA marks on the ectopically retained DNA sequence. Together, these results suggest that piRNA-guided 6mA DNA methylation leads to protection of DNA sequences against deletion during nuclear differentiation. Highlights DNA N6-methyladenine accumulates on retained DNA regions during Oxytricha development. mta1 mutant backcrosses have disrupted DNA methylation and a developmental delay. DNA N6-adenine methylation during genome rearrangement requires the presence of Otiwi1. Programmed retention of a germline-limited region leads to developmental methylation.

  PublisherOA PDFDOI

• Relaxed DNA substrate specificity of transposases involved in programmed genome rearrangement

  Nucleic Acids Research · 2025-06-13 · 2 citations

  articleOpen accessSenior author

  During post-zygotic development, the ciliate Oxytricha trifallax undergoes massive programmed genome rearrangement that involves over 225 000 DNA cleavage and joining events. An Oxytricha family of Tc1/mariner transposons, known as telomere-bearing elements (TBEs), encodes a transposase that has been implicated in rearrangement, but its high copy number (>34 000 paralogs) has precluded genetic strategies to investigate its DNA recognition properties directly in Oxytricha. Here, we developed a heterologous strategy to assay TBE transposase expression and activity in Escherichia coli, revealing highly promiscuous DNA cleavage properties. Systematic ChIP-seq experiments allowed us to define the DNA binding specificities of multiple distinct transposase subfamilies, which exhibited a binding and cleavage preference for short, degenerate sequence motifs that resemble features present within the TBE transposon ends. The relaxed sequence preference is striking for autonomous transposases, which typically recognize their end sequences with strict specificity to avoid compromising host fitness. Finally, we developed a custom antibody to investigate TBE transposases in their native environment and found that they precisely localize to the developing nucleus exclusively during the rearrangement process. Collectively, this work establishes a robust heterologous workflow for the biochemical investigation of enzymes that have been repurposed for large-scale genome rearrangements.

  PublisherOA PDFDOI

• Relaxed DNA substrate specificity of transposases involved in programmed genome rearrangement

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-18

  preprintOpen accessSenior authorCorresponding

  ABSTRACT During post-zygotic development, the ciliate Oxytricha trifallax undergoes massive programmed genome rearrangement that involves over 225,000 DNA cleavage and joining events. An Oxytricha family of Tc 1/mariner transposons, known as Telomere-Bearing Elements (TBEs), encodes a transposase that has been implicated in rearrangement, but its high copy number (&gt;34,000 paralogs) has precluded genetic strategies to investigate its DNA recognition properties directly in Oxytricha . Here, we developed a heterologous strategy to assay TBE transposase expression and activity in E. coli , revealing highly promiscuous DNA cleavage properties. Systematic ChIP-seq experiments allowed us to define the DNA binding specificities of multiple distinct transposase subfamilies, which exhibited a binding and cleavage preference for short, degenerate sequence motifs that resemble features present within the TBE transposon ends. The relaxed sequence preference is striking for autonomous transposases, which typically recognize their end sequences with strict specificity to avoid compromising host fitness. Finally, we developed a custom antibody to investigate TBE transposases in their native environment and found that they precisely localize to the developing nucleus exclusively during the rearrangement process. Collectively, this work establishes a robust heterologous workflow for the biochemical investigation of enzymes that have been repurposed for large-scale genome rearrangements.

  PublisherOA PDFDOI

• Widespread 3D genome reorganization precedes programmed DNA rearrangement in <i>Oxytricha trifallax</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Genome organization recapitulates function, yet ciliates like Oxytricha trifallax possess highly-specialized germline genomes, which are largely transcriptionally silent. During post-zygotic development, Oxytricha ’s germline undergoes large-scale genome editing, rearranging precursor genome elements into a transcriptionally-active genome with thousands of gene-sized nanochromosomes. Transgenerationally-inherited RNAs, derived from the parental somatic genome, program the retention and reordering of germline fragments. Retained and eliminated DNA must be distinguished and processed separately, but the role of chromatin organization in this process is unknown. We developed tools for studying Oxytricha nuclei and apply them to map the 3D organization of precursor and developmental states using Hi-C. We find that the precursor conformation primes the germline for development, while a massive spatial reorganization during development differentiates retained from eliminated regions before DNA rearrangement. Further experiments suggest a role for RNA-DNA interactions and chromatin remodeling in this process, implying a critical role for 3D architecture in programmed genome rearrangement.

  PublisherOA PDFDOI

• Exploration of the Nuclear Proteomes in the Ciliate Oxytricha trifallax

  Microorganisms · 2023-01-30 · 3 citations

  articleOpen accessSenior authorCorresponding

  Nuclear dimorphism is a fundamental feature of ciliated protozoa, which have separate somatic and germline genomes in two distinct organelles within a single cell. The transcriptionally active somatic genome, contained within the physically larger macronucleus, is both structurally and functionally different from the silent germline genome housed in the smaller micronucleus. This difference in genome architecture is particularly exaggerated in Oxytricha trifallax, in which the somatic genome comprises tens of thousands of gene-sized nanochromosomes maintained at a high and variable ploidy, while the germline has a diploid set of megabase-scale chromosomes. To examine the compositional differences between the nuclear structures housing the genomes, we performed a proteomic survey of both types of nuclei and of macronuclear histones using quantitative mass spectrometry. We note distinct differences between the somatic and germline nuclei, with many functional proteins being highly enriched in one of the two nuclei. To validate our conclusions and the efficacy of nuclear separation, we used protein localization through a combination of transformations and immunofluorescence. We also note that the macronuclear histones strikingly display only activating marks, consistent with the conclusion that the macronucleus is the hub of transcription. These observations suggest that the compartmentalization of different genome features into separate structures has been accompanied by a similar specialization of nuclear components that maintain and facilitate the functions of the genomes specific to each nucleus.

  PublisherOA PDFDOI

• SDRAP for annotating scrambled or rearranged genomes

  NAR Genomics and Bioinformatics · 2023-10-04 · 2 citations

  articleOpen access

  Genomes sometimes undergo large-scale rearrangements. Programmed genome rearrangements in ciliates offer an extreme example, making them a compelling model system to study DNA rearrangements. Currently, available methods for genome annotation are not adequate for highly scrambled genomes. We present a theoretical framework and software implementation for the systematic extraction and analysis of DNA rearrangement annotations from pairs of genome assemblies corresponding to precursor and product versions. The software makes no assumptions about the structure of the rearrangements, and permits the user to select parameters to suit the data. Compared to previous approaches, this work achieves more complete precursor-product mappings, allows for full transparency and reproducibility, and can be adapted to genomic data from different sources.

  PublisherOA PDFDOI

• Additional file 3 of NT-seq: a chemical-based sequencing method for genomic methylome profiling

  Figshare · 2022-01-01

  datasetOpen access

  Additional file 3: Table S2. Nitrite treatment condition optimization by qPCR.

  PublisherDOI

• Additional file 6 of NT-seq: a chemical-based sequencing method for genomic methylome profiling

  Figshare · 2022-01-01

  datasetOpen access

  Additional file 6: Table S5. Oligos and primers used in this study.

  PublisherDOI

• Additional file 2 of NT-seq: a chemical-based sequencing method for genomic methylome profiling

  Figshare · 2022-01-01

  datasetOpen access

  Additional file 2: Table S1. Comparison between protected and unprotected oligo under the same nitrite treatment.

  PublisherDOI

• Additional file 5 of NT-seq: a chemical-based sequencing method for genomic methylome profiling

  Figshare · 2022-01-01

  datasetOpen access

  Additional file 5: Table S4. PCR duplication rate of unenriched and 6mA DIP enriched library.

  PublisherDOI

Recent grants

• Understanding Complex Genome Editing and RNA Biology in Oxytricha

  NIH · $7.1M · 2017–2027

• Molecular Computation in Ciliates

  NSF · $918k · 2006–2010

• Collaborative Research: Discrete and Topological Models for Template-Guided Genome Rearrangements

  NSF · $570k · 2018–2022

• Epigenetic Mechanisms for the Inheritance of Acquired Mutations

  NSF · $808k · 2009–2012

• RNA Biology in Oxytricha: a Complex Unicellular Model

  NIH · $608k · 2015–2019

Frequent coauthors

• Jody Hey

  149 shared

• Dan Graur

  University of Houston

  149 shared

• Paul M. Sharp

  University of Edinburgh

  149 shared

• Jianzhi Zhang

  Fuzhou University

  149 shared

• John M. Archibald

  Dalhousie University

  149 shared

• Michael Lynch

  Urbana University

  149 shared

• Ziheng Yang

  Sichuan Agricultural University

  145 shared

• Marcy K. Uyenoyama

  Duke University

  85 shared

Labs

• Landweber LabPI

Education

• Ph.D.

  Harvard University

  1993

• Other

  Princeton University

  1994

Awards & honors

• Guggenheim fellowship (2012)
• Blavatnik award for young scientists (2008)
• Fellow of AAAS (2005)
• President, Society for Molecular Biology and Evolution (2017…