RT Journal
A1 Lal, Avantika
A1 Garfield, David
A1 Biancalani, Tommaso
A1 Eraslan, Gokcen
T1 Designing realistic regulatory DNA with autoregressive language models
JF Genome Research 
JO Genome Research 
YR 2024 
FD September 01 
VO 34 
IS 9 
SP 1411 
OP 1420 
DO 10.1101/gr.279142.124 
UL http://genome.cshlp.org/content/34/9/1411.abstract 
AB Cis-regulatory elements (CREs), such as promoters and enhancers, are DNA sequences that regulate the expression of genes. The activity of a CRE is influenced by the order, composition, and spacing of sequence motifs that are bound by proteins called transcription factors (TFs). Synthetic CREs with specific properties are needed for biomanufacturing as well as for many therapeutic applications including cell and gene therapy. Here, we present regLM, a framework to design synthetic CREs with desired properties, such as high, low, or cell type–specific activity, using autoregressive language models in conjunction with supervised sequence-to-function models. We used our framework to design synthetic yeast promoters and cell type–specific human enhancers. We demonstrate that the synthetic CREs generated by our approach are not only predicted to have the desired functionality but also contain biological features similar to experimentally validated CREs. regLM thus facilitates the design of realistic regulatory DNA elements while providing insights into the cis-regulatory code.