Kaessmann Lab

It was a wonderful opportunity to reflect on our work on the development of the mammalian cerebellum.

We thank our editors, Alexandra Joyner and James Li!

Special thanks to Henrik @kaessmannlab.bsky.social for his unwavering support and mentorship!

How have concerted and mosaic evolutionary mechanisms shaped the expansion of the human cerebellum?

Our review with @tyamadat.bsky.social and @ioansarr.bsky.social available free till March 29:
authors.elsevier.com/a/1ma2wFzn7a...

We hope our data can be useful to you, and to increase its usability, we've generated an exploratory web app as a resource and starting point to examine our data on the @kaessmannlab.bsky.social website apps.kaessmannlab.org/HindbrainExp...

Brain with puzzle overlay to show that our study provides missing pieces of the puzzle of human brain development by delivering the most comprehensive picture of hindbrain development to date. We have strived to go beyond just another multi-omics atlas to gain deep insights by: 1. Meticulously annotating cell clusters 2. Extracting regulatory programs in terms of coordinated gene sets and accessible regulatory elements 3. Using deep learning to identify regulatory syntax 4. Resolving context-specific TF activity

Excited to share our preprint on our new multi-omic atlas of human hindbrain development. Led by postdoc Piyush Joshi, in collaboration with @kaessmannlab.bsky.social and Pfister labs, our atlas represents the first comprehensive view of human hindbrain development. www.biorxiv.org/content/10.6...

Many thanks for your - as always - super valuable contributions!❤️

Many thanks Mary Beth!

Using AI to Retrace the Evolution of Genetic Control Elements in the Brain – Researchers map evolutionary changes in the developing mammalian cerebellum www.uni-heidelberg.de/en/newsroom/...

Many thanks Cedric!

Many thanks Pradeepa! Hope all is well!

Thanks a lot!

Many thanks!

Fantastic opportunity - Mari is an exceptional scientist and person and was an outstanding pillar of our lab!

I've started my own lab 🎉
PhD/postdoc positions available - reach out if curious about cerebellum evo-devo and autism spectrum disorders.

We’re based at Uni Tartu, Institute of Genomics (home to Estonian Biobank), and funded by @simonsfoundation.org @embo.org, and the Estonian Research Council.

Thank you!

Thanks so much Stein for the wonderful collaboration!!

We are thrilled that our study on the evolution of gene regulation in mammalian cerebellum development – led by @ioansarr.bsky.social, @marisepp.bsky.social and @tyamadat.bsky.social, in collaboration with @steinaerts.bsky.social – is now out in @ScienceMagazine! www.science.org/doi/10.1126/...

Thank you!

Thanks so much Rob!

Our study presents the first comprehensive, cell type-resolved analysis of TE regulatory co-option across primate evolution, revealing how TEs contribute to species-specific regulatory divergence and phenotypic evolution.

Species-specific accessible HERVL copies contribute to divergent gene expression patterns – including elevated expression of neurodevelopmentally relevant genes such as C9orf72 and MGST2 in humans.

Comparative analysis across primates and mouse show that although the regulatory potential for HERVL co-option is conserved, different HERVL copies become accessible in each species, creating lineage-specific regulatory landscapes.

Accessibility of individual HERVL copies is governed by two complementary factors: the preservation of transcription factor binding motifs and positioning within active chromatin neighborhoods.

Luciferase reporter assays using consensus sequences of HERVL and related TEs demonstrated that HERVL specifically exhibits enhancer activity in primary cultures of mouse granule cells.

We discovered that HERVLs – primate-specific retrotransposons – are preferentially co-opted as regulatory elements in cerebellar granule cells and other rhombic lip-derived neuroblasts in the pons and medulla, facilitated by the presence of sequences that resemble ATOH1 and NFI binding motifs.

Our deep learning-based pipeline systematically screened TE fragments for regulatory potential, and identified 17 TE subfamilies whose ancestral sequences contain cis-regulatory motifs that resemble those found in elements accessible in cerebellar cells.

We found that TEs are significantly enriched in species- and cell type-specific elements – particularly in later-developing, less constrained cell types. This pattern is further supported by datasets spanning multiple human organs across development.

By combining comprehensive single-cell multiomics atlases of mammalian cerebellum development with deep learning-based modeling of enhancer grammar, we systematically investigated how TEs contribute to gene regulatory programs across developing cerebellar cell types.

However, their contribution to mammalian organ development at the cellular level has remained largely unexplored, owing to the lack of cell type-resolved datasets and suitable analytical frameworks.

TEs make up nearly half of the human genome and have long been hypothesized to drive gene expression innovation through their capacity to rewire regulatory networks.

In that study, we traced evolutionary history of human cis-regulatory elements (CREs) and highlighted many candidate CRE innovations from single-nucleotide substitutions or small insertions and deletions (indels). But what about TEs?