PROJECT SUMMARY/ABSTRACT with changes for year5 extension (underlined) It is said that if the genome represents the set of things that the cell could say, then the transcriptome represents the set of things that the cell is saying right now. The transcriptome is the primary read-out of the genome and is composed mainly of mRNAs, long noncoding RNAs, and microRNAs. At all stages of life, in health and in disease, differences in the transcriptome causally define and distinguish each cell type and cell state. The mission of the ENCODE Consortium is to discover, map and define all genes and their regulatory elements. RNA-Seq data and the resulting transcriptomes have therefore been a prominent component of prior phases of ENCODE, and our groups have contributed over 350 released poly(A) mRNA and microRNA datasets for the project. Valuable and high quality as those data are, new technologies will allow us to produce a new generation of transcriptomes that are much more information rich and definitive. Specifically, they resolve the multiple different cell types that comprise complex tissues and they resolve the multiple molecular isoforms. They document long-range single molecule splicing and end processing and we provide companion quantification of microRNAs, plus discovery of their often-undocumented precursor RNAs. Finally, we map RNA secondary structure across the transcriptome in vivo. We propose to complete contributing at least 200 higher precision long-read transcriptomes and companion measurement types, and their integrated analysis. We also add short- read ribo-minus RNA-seq across the NHGRI approved consortium biosamples. A portion of this study focuses on aging humans and mice, a whole life cycle stage that has not previously been studied in ENCODE. The corresponding disease component contrasts cognitively normal with Alzheimer’s dementia.