A method of preparing a sequencing library for determining the methylation status of nucleic acids from a plurality of single cells, the method comprising: (a) providing isolated nuclei from a plurality of cells; (b) subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei, while maintaining integrity of the isolated nuclei; (c) distributing subsets of the nucleosome-depleted nuclei into a first plurality of compartments comprising a transposome complex, wherein the transposome complex in each compartment comprises a first index sequence that is different from first index sequences in the other compartments; (d) fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments and incorporating the first index sequences into at least one strand of the nucleic acid fragments to generate indexed nuclei; (e) combining the indexed nuclei to generate pooled indexed nuclei; (f) distributing subsets of the pooled indexed nuclei into a second plurality of compartments and subjecting the indexed nuclei to treatment to identify methylated nucleotides and to generate treated nucleic acid fragments, optionally wherein the treatment comprises bisulfite or hydrazine; (g) amplifying the treated nucleic acid fragments in each compartment by linear amplification with a plurality of primers comprising a universal nucleotide sequence at the 5' end and a random nucleotide sequence at the 3' end to generate amplified fragment-adapter molecules; (h) incorporating a second index sequence into the amplified fragment-adapter molecules to generate dual-index fragment-adapter molecules, wherein the second index sequence in each compartment is different from second index sequences in the other compartments; and (i) combining the dual-index fragment-adapter molecules, thereby producing a sequencing library for determining the methylation status of nucleic acids from the plurality of single cells, optionally wherein the distributing in steps (c) and (f) is performed by fluorescence-activated nuclei sorting. (a) providing isolated nuclei from a plurality of cells; (b) subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei, while maintaining integrity of the isolated nuclei; (c) distributing subsets of the nucleosome-depleted nuclei into a first plurality of compartments comprising a transposome complex, wherein the transposome complex in each compartment comprises a first index sequence that is different from first index sequences in the other compartments; (d) fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments and incorporating the first index sequences into at least one strand of the nucleic acid fragments to generate indexed nuclei; (e) combining the indexed nuclei to generate pooled indexed nuclei; (f) distributing subsets of the pooled indexed nuclei into a second plurality of compartments and subjecting the indexed nuclei to treatment to identify methylated nucleotides and to generate treated nucleic acid fragments, optionally wherein the treatment comprises bisulfite or hydrazine; (g) amplifying the treated nucleic acid fragments in each compartment by linear amplification with a plurality of primers comprising a universal nucleotide sequence at the 5' end and a random nucleotide sequence at the 3' end to generate amplified fragment-adapter molecules; (h) incorporating a second index sequence into the amplified fragment-adapter molecules to generate dual-index fragment-adapter molecules, wherein the second index sequence in each compartment is different from second index sequences in the other compartments; and (i) combining the dual-index fragment-adapter molecules, thereby producing a sequencing library for determining the methylation status of nucleic acids from the plurality of single cells, optionally wherein the distributing in steps (c) and (f) is performed by fluorescence-activated nuclei sorting.